Phosphoinositide 3-kinase inhibitors with a zinc binding moiety

ABSTRACT

The instant application relates to deazapurines, thienopyrimidines and furopyrimidines with zinc-binding moiety based derivatives and their use in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Applications No.61/143,271, filed Jan. 8, 2009, and 61/172,580, filed Apr. 24, 2009. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Phosphoinositides (PIs), which are phosphorylated derivatives ofphosphatidylinositol, are essential in eukaryotic cells, regulatingnuclear processes, cytoskeletal dynamics, signalling and membranetrafficking Among the enzymes involved in PI metabolism, PI3-kinases(PI3K) have attracted special attention because of their oncogenicproperties and potential as drug targets. PI3-kinases phosphorylatephosphatidylinositols or PIs at the 3-position of the inositol ring.(Lindmo et. al. Journal of Cell Science 119, 605-614, 2006). The3-phosphorylated phospholipids generated by PI3K activity bind to thepleckstrin homology (PH) domain of protein kinase B (PKB), causingtranslocation of PKB to the cell membrane and subsequent phosphorylationof PKB. Phosphorylated PKB inhibits apoptosis-inducing proteins such asFKHR, Bad, and caspases, and is thought to play an important role incancer progression. The PI3Ks are divided into classes I-III, and classI is further subclassified into classes Ia and Ib. Among these isoforms,class Ia enzymes are thought to play the most important role in cellproliferation in response to growth factor-tyrosine kinase pathwayactivation (Hayakawa et. al., Bioorganic & Medicinal Chemistry 146847-6858, 2006). Three frequent mutations in cancer constitutivelyactivate PI3Kα and, when expressed in cells, they drive the oncogenictransformation and chronic activation of downstream signalling bymolecules such as PKB, S6K and 4E bp1 that is commonly seen in cancercells. (Stephens et. al., Current Opinion in Pharmacology, 5(4) 357-365,2005). As such, PI3-kinases are attractive targets for the treatment ofproliferative diseases.

There are several known PI3-kinase inhibitors including Wortmannin andLY294002. Although wortmannin is a potent PI3K inhibitor with a lownanomolar IC₅₀ value, it has low in vivo anti-tumor activity. (Hayakawaet al, Bioorg Med Chem 14(20), 6847-6858 (2006)). Recently, a group ofmorpholine substituted quinazoline, pyridopyrimidine andthienopyrimidine compounds have been reported to be effective ininhibiting PI3kinase p110α. (Hayakawa, 6847-6858). Oral dosage of amorpholine substituted thienopyrimidine compound (GDC-0941) has showntumor suppression in glioblastoma xenografts in vivo. (Folkes et. al.,Journal of Medicinal Chemistry, 51, 5522-5532, 2008). The followingpublications disclose a series of thienopyrimidine, pyridopyrimidine andquinazoline based PI3-Kinase inhibitors: WO 2008/073785; WO 2008/070740;WO 2007/127183; U.S. Patent Publication 20080242665.

Histone acetylation is a reversible modification, with deacetylationbeing catalyzed by a family of enzymes termed histone deacetylases(HDACs). HDAC's are represented by 18 genes in humans and are dividedinto four distinct classes (J Mol Biol, 2004, 338:1, 17-31). Inmammalians class I HDAC's (HDAC1-3, and HDAC8) are related to yeast RPD3HDAC, class 2 (HDAC4-7, HDAC9 and HDAC10) related to yeast HDA1, class 4(HDAC11), and class 3 (a distinct class encompassing the sirtuins whichare related to yeast Sir2).

Csordas, Biochem. J., 1990, 286: 23-38 teaches that histones are subjectto post-translational acetylation of the, ε-amino groups of N-terminallysine residues, a reaction that is catalyzed by histone acetyltransferase (HAT1). Acetylation neutralizes the positive charge of thelysine side chain, and is thought to impact chromatin structure. Indeed,access of transcription factors to chromatin templates is enhanced byhistone hyperacetylation, and enrichment in underacetylated histone H4has been found in transcriptionally silent regions of the genome(Taunton et al., Science, 1996, 272:408-411). In the case of tumorsuppressor genes, transcriptional silencing due to histone modificationcan lead to oncogenic transformation and cancer.

Several classes of HDAC inhibitors currently are being evaluated byclinical investigators. Examples include hydroxamic acid derivatives,Suberoylanilide hydroxamic acid (SAHA), PXD101 and LAQ824, are currentlyin the clinical development. In the benzamide class of HDAC inhibitors,MS-275, MGCD0103 and CI-994 have reached clinical trials. Mourne et al.(Abstract #4725, AACR 2005), demonstrate that thiophenyl modification ofbenzamides significantly enhance HDAC inhibitory activity against HDAC1.

Mammalian Target of Rapamycin (mTOR) is a signaling protein which isdownstream of multiple signaling pathways, including the PI3K/Aktpathway. Cell signaling through mTOR controls a variety of cellularresponses, including responses to nutrients and growth factors. mTORinhibitors are currently in clinical use for the prevention oftransplant rejection. However, the ability of these compounds to shrinktumors suggests their potential use as anti-cancer agents. The effect ofmTOR inhibitors on cancer cells may arise from inhibition of the PI3/Aktpathway. Inhibition of mTOR also lowers VEGF levels, resulting in anantiangiogenic effect that may also contribute to tumor shrinkage.Recent research suggests that the inhibition of multiple targets in thePI3K/Akt pathway provides improved anticancer activity. Thus, compoundswhich inhibit both PI3K and mTOR are desirable.

Certain cancers have been effectively treated with such a combinatorialapproach; however, treatment regimes using a cocktail of cytotoxic drugsoften are limited by dose limiting toxicities and drug-druginteractions. More recent advances with molecularly targeted drugs haveprovided new approaches to combination treatment for cancer, allowingmultiple targeted agents to be used simultaneously, or combining thesenew therapies with standard chemotherapeutics or radiation to improveoutcome without reaching dose limiting toxicities. However, the abilityto use such combinations currently is limited to drugs that showcompatible pharmacologic and pharmacodynamic properties. In addition,the regulatory requirements to demonstrate safety and efficacy ofcombination therapies can be more costly and lengthy than correspondingsingle agent trials. Once approved, combination strategies may also beassociated with increased costs to patients, as well as decreasedpatient compliance owing to the more intricate dosing paradigmsrequired.

SUMMARY OF THE INVENTION

The present invention relates to deazapurines, thienopyrimidines andfuropyrimidines with zinc-binding moiety based derivatives and their usein the treatment of PI3K related diseases and disorders such as cancer.The compounds of the present invention may further act as HDAC or matrixmetalloproteinase (MMP) inhibitors by virtue of their ability to bindzinc ions. Surprisingly these compounds are active at multipletherapeutic targets and are effective for treating disease. Moreover, insome cases it has even more surprisingly been found that the compoundshave enhanced activity when compared to the activities of combinationsof separate molecules individually having the PI3-Kinase and HDACactivity. In other words, the combination of PI3-kinases and HDACinhibitors into a single molecule may provide a synergistic effect ascompared to the PI3-kinases. In another embodiment, certain compounds ofthe present invention also inhibit mTor in addition to having PI3-Kinaseand HDAC activity.

Accordingly, one aspect of the present invention provides a compoundhaving the general formula (I):

-   or a geometric isomer, enantiomer, diastereomer, racemate,    pharmaceutically acceptable salt or prodrug thereof,-   wherein    represents a single or double bond;-   q, r and s are independently 0 or 1, wherein at least one of q, r    and s is 1; preferably, one of q, r and s is 1 and the rest are 0;-   n is 0, 1, 2, 3 or 4;-   p is 0, 1 or 2, preferably 0 or 1;-   t is 0 or 1; preferably, when s is 1, t is 0;-   X and Y are independently CR₁, N(R₈), S or O; wherein when one of X    and Y is CR₁, the other is N(R₈), S or O; preferably X is S and Y is    CR₁;-   G₁ is CR₁, S, O, NR₁₀ or NS(O)₂R_(10;)-   G₂ is substituted or unsubstituted aryl, substituted or    unsubstituted heteroaryl or, substituted or unsubstituted    heterocyclic;-   G₃ is substituted or unsubstituted C₁-C₈ alkyl, substituted or    unsubstituted C₂-C₈ alkenyl or substituted or unsubstituted C₂-C₈    alkynyl;-   each R₈ is independently hydrogen, acyl, aliphatic or substituted    aliphatic;-   each R₁ and R₂ is absent or is independently selected from hydrogen,    hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN,    NO₂, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl,    substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,    and substituted heterocyclic;-   R_(a) is optionally substituted alkyl, optionally substituted aryl    or optionally substituted heteroaryl;-   R_(b) is hydrogen, optionally substituted alkyl, optionally    substituted aryl or optionally substituted heteroaryl;-   or R_(a) and R_(b), together with the nitrogen atom to which they    are attached, form an optionally substituted heterocyclic group;-   R₁₀ is selected from hydrogen, hydroxy, amino, alkoxy, alkylamino,    dialkylamino, sulfonyl, acyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heteroaryl, substituted heteroaryl,    heterocyclic, and substituted heterocyclic; preferably R₁₀ is    hydrogen, acyl, aliphatic or substituted aliphatic;-   B is a linker; and-   C is selected from:

-   -   where W is O or S; J is O, NH or NCH₃; and R₃₁ is hydrogen or        lower alkyl;

-   -   where W is O or S; Y₂ is absent, N, or CH; Z is N or CH; R₃₂ and        R₃₄ are independently hydrogen, hydroxy, aliphatic group,        provided that if R₃₂ and R₃₄ are both present, one of R₃₂ or R₃₄        must be hydroxy and if Y₂ is absent, R₃₄ must be hydroxy; and        R₃₃ is hydrogen or aliphatic group;

-   -   where W is O or S; Y₁ and Z₁ are independently N, C or CH; and

-   -   where Z, Y₂, and W are as previously defined; R₁₁ and R₁₂ are        independently selected from hydrogen or aliphatic; R₂₁, R₂₂ and        R₂₃ are independently selected from hydrogen, hydroxy, amino,        halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,        sulfonyl, acyl, aliphatic, substituted aliphatic, aryl,        substituted aryl, heteroaryl, substituted heteroaryl,        heterocyclic, and substituted heterocyclic.

In another embodiment, each R₁ and R₂ is independently absent, hydrogen,hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic; arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, heterocyclylalkyl or substitutedheterocyclylalkyl.

Another aspect of the invention provides methods of inhibiting PI3kinase activity, by contacting a PI3 kinase with an effective inhibitoryamount of a compound of Formula I, or a stereoisomer, geometric isomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the compounds of the present invention arecompounds represented by formulae (I) as illustrated above, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof.

In one embodiment, the compounds of the present invention are compoundsrepresented by formula (II) or formula (III), or a geometric isomer,enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, orprodrug thereof:

wherein

represents a single or double bond and G₁, G₂, G₃, R₁, R₂, X, Y, n, p,q, r, s, B and C are as defined above. Preferably, in Formula (III), qis 1 and r is 0.

In another embodiment of the compounds of the present invention arecompounds represented by formula (IV) and (V) as illustrated below, orits geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, and prodrugs thereof:

wherein

represents a single or double bond; G₁, G₂, R₁, R₂, R₈, n, p, q, r, s, Band C are as defined above; and G₄ is NR₈, S or O, preferably S.Preferably G₁ is O.

In another embodiment of the compounds of the present invention arecompounds represented by formula (VI) or (VII) as illustrated below, andthe geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, and prodrugs thereof:

wherein

represents a single or double bond; G₁, G₄, R₁, R₂, R₈, n, p, q, r, s, Band C are as defined above; m is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and R₃is selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy,alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl, aliphatic,substituted aliphatic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic.

In another embodiment of the compounds of the present invention arecompounds represented by formula (VIII) and (IX) as illustrated below,or the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, and prodrugs thereof:

wherein

represents a single or double bond; G₁, G₄, R₁, R₂, R₃, R₈, n, m, p, q,s, B and C are as defined above; and o is 1, 2, 3 or 4.

In preferred embodiments of the compounds of Formulas I, II, IV, V, VIand VII, q and r are 0 and s is 1. In another preferred embodiment q is1 while r and s are 0. In another preferred embodiment q and s are 0 andr is 1.

In preferred embodiments of the compounds of Formula III, r is 0 and qis 1.

In preferred embodiments of the compounds of Formulas VIII and IX, q is1 and s is 0.

In a preferred embodiment, B is a C₁-C₈ alkyl where one or more CH₂ canbe optionally replaced by O, S, SO₂, NR₈ or —CONH—, C is —C(O)N(H)OH,and G₁ is —O. In another preferred embodiment, B is a C₁-C₈ alkyl whereone or more CH₂ can be optionally replaced by O, S, SO₂, NR₈ or —CONH—,C is —C(O)N(H)OH, and G₁ is —NS(O)₂CH₃. In another preferred embodiment,B is an aryl, heteroaryl, C₁-C₁₀-alkylaryl, C₁-C₁₀-alkylheteroarylgroup, C₁-C₁₀-alkylheterocyclylaryl, C₁-C₁₀-alkylheterocyclylheteroaryl,C₁-C₁₀-alkylheterocyclylaryl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylheterocyclylheteroaryl-C₁-C₁₀-alkyl group where one or moreCH₂ can be optionally replaced by O, S, SO₂, NR₈ or —CONH—, and G₁ is —Oor —NS(O)₂CH₃.

In another embodiment of the compounds of the present invention arecompounds represented by formula (X) and (XI) as illustrated below, orthe geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts or prodrugs thereof:

wherein

represents a single or double bond; G₁, G₂, G₄, R_(a), R_(b), R₁, R₂, n,p, q, s, B and C are as defined above; and o is 1, 2, 3 or 4. Inpreferred embodiments, G₂ is optionally substituted phenyl, pyridyl,pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl,pyrazolyl or benzimidazolyl.

In another embodiment of the compounds of the present invention arecompounds represented by formula (XII) and (XIII) as illustrated below,or the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts or prodrugs thereof:

wherein

represents a single or double bond; G₁, G₄, R_(a), R_(b), R₁, R₂, R₃,R₈, n, p, q, r, s, B and C are as defined above; m is 0, 1, 2 or 3; ando is 1, 2, 3 or 4.

In a preferred embodiment of the compounds of Formulas X-XIII, q is 0and s is 1. In another preferred embodiment, q is 1 and s is 0. In apreferred embodiment, B is a C₁-C₈ alkyl where one or more CH₂ can beoptionally replaced by O, S, SO₂, NR₈ or —CONH—, C is —C(O)N(H)OH, andG₁ is —O. In another preferred embodiment, B is a C₁-C₈ alkyl where oneor more CH₂ can be optionally replaced by O, S, SO₂, NR₈ or —CONH—, C is—C(O)N(H)OH, and G₁ is —NS(O)₂CH₃.

In another embodiment of the compounds of the present invention arecompounds represented by formula XIV and XV as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts or prodrugs thereof:

wherein G₁, G₂, n, p, B, C, R₁ and R₂ are as defined above. In preferredembodiments, G₂ is optionally substituted phenyl, pyridyl, pyrimidyl,indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl orbenzimidazolyl.

In another embodiment of the compounds of the present invention arecompounds represented by formula XVI and XVII as illustrated below, orits geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts or prodrugs thereof:

wherein G₁, n, m, p, B, C, R₁, R₂, R₃ and R₈ are as defined above.

A preferred embodiment of the compounds of Formulas IX-XVII is where Bis a C₁-C₈ alkyl where one or more CH₂ can be optionally replaced by O,S, SO₂, N(R₈), —CONH—, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic groups, C is—C(O)N(H)OH, and G₁ is O. Another preferred embodiment is where B is aC₁-C₈ alkyl where one or more CH₂ can be optionally replaced by O, S,SO₂, NR₈, —CONH—, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic groups, C is—C(O)N(H)OH, and G₁ is —NS(O)₂CH₃.

In another embodiment of the compounds of the present invention arecompounds represented by formula XVIII or formula XIX, as illustratedbelow, or the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof:

wherein n, m, p, B, C, R₁, R₂, R₃, and R₈ are as defined above.

In another embodiment of the compounds of the present invention arecompounds represented by formula XX as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof:

wherein n, p, Y₂, W, Z, G₁, G₄, G₂, R₁, R₂, R₃, R₃₂, R₃₃ and R₃₄ are areas defined above; M₁ is absent, O, S, NR₈, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, aryl, heteroaryl, heterocyclic, SO, SO₂ or C═O; M₂ isabsent, C₁-C₆ alkyl, O, NR₈, heterocyclic, aryl, heteroaryl, or C═O; M₃is absent, O, NR₈, S, SO, SO₂, CO, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, heteroaryl, or heterocyclic; M₄ is absent, O, NR₈,heteroaryl, heterocyclic or aryl; and M₅ is absent, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, heteroaryl, heterocyclic or aryl. In preferredembodiments, G₂ is optionally substituted phenyl, pyridyl, pyrimidyl,indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, imidazolyl, pyrazolyl orbenzoimidazolyl. In more preferred embodiments, G₂ is optionallysubstituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl orbenzimidazolyl.

In another embodiment of the compounds of the present invention arecompounds represented by formula (XXI) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof:

wherein n, m, p, Y₂, W, Z, G₁, G₄, R₁, R₂, R₃, R₈, R₃₂, R₃₃, R₃₄ andM₁-M₅ are as defined above.

In a another embodiment of the compounds of the present invention arecompounds represented by formula (XXII) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof.

wherein G₁, G₂, G₄, n, p, R₁, R₂ and R₃ are as defined above; t, v and ware independently 0, 1, 2 or 3; u is 0, 1, 2, 3, 4, 5, 6, 7 or 8; G₅ isabsent, C₁-C₈ alkyl or a C₁-C₈ alkyl interrupted by one or more O, S,S(O), SO₂, N(R₈), or C(O); preferably G₅ is —N(R₈)—C₁-C₄-alkyl, t is 1and u is 0;

-   G₆ is selected from CR₁ or NR₈, wherein R₁ and R₈ are as defined    above;-   G₇ is selected from —CR₁, —NR₈, S or O wherein R₁ and R₈ are as    defined above; or-   G₇ is selected from —C(R₁)₂ , and —N; R₅ and R₆ are independently    selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy,    alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl, aliphatic,    substituted aliphatic, aryl, substituted aryl, heteroaryl,    substituted heteroaryl, heterocyclic, and substituted heterocyclic.    In preferred embodiments, G₂ is optionally substituted phenyl,    pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl,    imidazolyl, pyrazolyl or benzimidazolyl. In more preferred    embodiments, G₂ is optionally substituted phenyl, pyridyl,    pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl. Preferably, when    G₇ is CR₁ or N, the pyrimidine ring is directly bonded to G₇.

In a another embodiment of the compounds of the present invention arecompounds represented by Formula XXIII as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof:

wherein G₁, G₄, n, m, p, R₁, R₂, R₃, R₈, t, v, w, u, G₅, G₆, and G₇ areas defined above.

In a another embodiment of the compounds of the present invention arecompounds represented by formula (XXIV) as illustrated below, or thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof:

wherein G₁, G₂, G₄, G₅, n, p, w, u, R₁, R₂, R₃ and R₆ are as definedabove. In preferred embodiments, G₂ is optionally substituted phenyl,pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl,imidazolyl, pyrazolyl or benzimidazolyl. In more preferred embodiments,G₁ is O, G₂ is optionally substituted phenyl, pyridyl, pyrimidyl,indazolyl, pyrrolyl or benzimidazolyl, G₅ is —N(R₈)—C₁-C₄-alkyl and u is0.

In a another embodiment of the compounds of the present invention arecompounds represented by formula (XXV) as illustrated below, or thegeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, and prodrugs thereof:

In more preferred embodiments of the compounds of formulas I, II, III,IV, V, X, XI, XIV, XV, XVIII, XX, XXII and XXIV, G₂ is selected from thegroup:

Preferably in these groups, m is 1 and R₃ is hydroxyl, hydroxymethyl,amino, acylamino, such as acetylamino, or methylamino. In anotherpreferred embodiment, G₂ is selected from the groups shown below:

where R₃, R₈ and m are as defined above.

In certain preferred embodiments of the compounds of formulas I, II,III, IV, V, X, XI, XIV, XV, XVIII, XX, XXII and XXIV, G₂ is optionallysubstituted monoaryl or monoheteroaryl groups. In more preferredembodiments, G₂ is phenyl, pyridyl, pyrimidyl or pyrrolyl with one ormore substituents include but not limited to hydroxyl, hydroxymethyl,amino and substituted amino; G₁ is O, G₅ is —N(R₈)—C₁-C₄-alkyl and u is0. For example, G₂ can be phenyl, pyridyl, pyrimidyl or pyrrolylsubstituted by a hydroxyl, hydroxymethyl, acetylamino, amino ormethylamino group. Such compounds have significant inhibitory activitytoward mTOR, as well as PI3 kinase and HDAC.

The most preferred embodiment for C is:

where R₃₃ is selected from hydrogen and lower alkyl.

In a preferred embodiment, the bivalent B is a direct bond or straight-or branched-, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl,heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl,alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl,alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl,alkenylheteroarylalkyl, alkenylheteroarylalkenyl,alkenylheteroarylalkynyl, alkynylheteroarylalkyl,alkynylheteroarylalkenyl, alkynylheteroarylalkynyl,alkylheterocyclylalkyl, alkylheterocyclylalkenyl,alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl,alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl,alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl,alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl, which one ormore methylenes can be interrupted or terminated by O, S, S(O), SO₂,N(R₈), C(O), substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclic;such divalent B linkers include but are not limited to alkyl, alkenyl,alkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheterocyclylaryl,alkylheterocyclylarylalkyl, alkylheterocyclylheteroaryl,alkylheterocyclylheteroarylalkyl, alkoxyaryl, alkylaminoaryl,alkoxyalkyl, alkylaminoalkyl, alkylheterocycloalkyl,alkylheteroarylalkyl, alkylamino, N(R₈)alkenyl, N(R₈)alkynyl,N(R₈)alkoxyalkyl, N(R₈)alkylaminoalkyl, N(R₈)alkylaminocarbonyl,N(R₈)alkylaryl, N(R₈)alkenylaryl, N(R₈)alkynylaryl, N(R₈)alkoxyaryl,N(R₈)alkylaminoaryl, N(R₈)cycloalkyl, N(R₈)aryl, N(R₈)heteroaryl,N(R₈)heterocycloalkyl, N(R₈)alkylheterocycloalkyl, alkoxy, O-alkenyl,O-alkynyl, O-alkoxyalkyl, O-alkylaminoalkyl, O-alkylaminocarbonyl,O-alkylaryl, O-alkenylaryl, O-alkynylaryl, O-alkoxyaryl,O-alkylaminoaryl, O-cycloalkyl, O-aryl, O-heteroaryl,O-heterocycloalkyl, O-alkylheterocycloalkyl, C(O)alkyl, C(O)-alkenyl,C(O)alkynyl, C(O)alkylaryl, C(O)alkenylaryl, C(O)alkynylaryl,C(O)alkoxyalkyl, C(O)alkylaminoalkyl, C(O)alkylaminocarbonyl,C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CON(R₈),CON(R₈)alkyl, CON(R₈)alkenyl, CON(R₈)alkynyl, CON(R₈)alkylaryl,CON(R₈)alkenylaryl, CON(R₈)alkynylaryl, CON(R₈)alkoxyalkyl,CON(R₈)alkylaminoalkyl, CON(R₈)alkylaminocarbonyl, CON(R₈)alkoxyaryl,CON(R₈)alkylaminoaryl, CON(R₈)cycloalkyl, CON(R₈)aryl,CON(R₈)heteroaryl, CON(R₈)heterocycloalkyl,CON(R₈)alkylheterocycloalkyl, N(R₈)C(O)alkyl, N(R₈)C(O)alkenyl,N(R₈)C(O)-alkynyl, N(R₈)C(O)alkylaryl, N(R₈)C(O)alkenylaryl,N(R₈)C(O)alkynylaryl, N(R₈)C(O)alkoxyalkyl, N(R₈)C(O)alkylaminoalkyl,N(R₈)C(O)alkylaminocarbonyl, N(R₈)C(O)alkoxyaryl,N(R₈)C(O)alkylaminoaryl, N(R₈)C(O)cycloalkyl, N(R₈)C(O)aryl,N(R₈)C(O)heteroaryl, N(R₈)C(O)heterocycloalkyl,N(R₈)C(O)alkylheterocycloalkyl, NHC(O)NH, NHC(O)NH-alkyl,NHC(O)NH-alkenyl, NHC(O)NH-alkynyl, NHC(O)NH-alkylaryl,NHC(O)NH-alkenylaryl, NHC(O)NH-alkynylaryl, NHC(O)NH-alkoxyaryl,NHC(O)NH-alkylaminoaryl, NHC(O)NH-cycloalkyl, NHC(O)NH-aryl,NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl,NHC(O)NH-alkylheterocycloalkyl, S-alkyl, S-alkenyl, S-alkynyl,S-alkoxyalkyl, S-alkylaminoalkyl, S-alkylaryl, S-alkylaminocarbonyl,S-alkylaryl, S-alkynylaryl, S-alkoxyaryl, S-alkylaminoaryl,S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl,S-alkylheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl,S(O)alkoxyalkyl, S(O)alkylaminoalkyl, S(O)alkylaminocarbonyl,S(O)alkylaryl, S(O)alkenylaryl, S(O)alkynylaryl, S(O)alkoxyaryl,S(O)alkylaminoaryl, S(O)cycloalkyl, S(O)aryl, S(O)heteroaryl,S(O)heterocycloalkyl, S(O)alkylheterocycloalkyl, S(O)₂alkyl,S(O)₂alkenyl, S(O)₂alkynyl, S(O)₂alkoxyalkyl, S(O)₂alkylaminoalkyl,S(O)₂alkylaminocarbonyl, S(O)₂alkylaryl, S(O)₂alkenylaryl,S(O)₂alkynylaryl, S(O)₂alkoxyaryl, S(O)₂alkylaminoaryl, S(O)₂cycloalkyl,S(O)₂aryl, S(O)₂heteroaryl, S(O)₂heterocycloalkyl,S(O)₂alkylheterocycloalkyl, S(O)₂heterocyclylalkyl,S(O)₂heterocyclylalkenyl, S(O)₂heterocyclylalkynyl, SO₂NH, SO₂NH-alkyl,SO₂NH-alkenyl, SO₂NH-alkynyl, SO₂NH-alkylaryl, SO₂NH-alkenylaryl,SO₂NH-alkynylaryl, SO₂NH-cycloalkyl, SO₂NH-aryl, SO₂NH-heteroaryl,SO₂NH-heterocycloalkyl, SO₂NH-alkylheterocycloalkyl, alkylaryloxyalkoxy,alkylaryloxyalkylamino, alkylarylaminoalkoxy, alkylarylaminoalkylamino,alkylarylalkylaminoalkoxy, alkylarylalkylaminoalkoxy,alkenylaryloxyalkoxy, alkenylaryloxyalkylamino, alkenylarylaminoalkoxy,alkenylarylaminoalkylamino, alkenylarylalkylaminoalkoxy,alkenylarylalkylaminoalkylamino.

In a more preferred embodiment, B is a straight chain alkyl, alkenyl,alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl,heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl,alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl,alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl,alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl,alkenylheteroarylalkenyl, alkenylheteroarylalkynyl,alkynylheteroarylalkyl, alkynylheteroarylalkenyl,alkynylheteroarylalkynyl, alkylheterocyclylalkyl,alkylheterocyclylalkenyl, alkylhererocyclylalkynyl,alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl,alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl,alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, oralkynylhereroaryl. One or more methylenes can be interrupted orterminated by —O—, —N(R₈)—, —C(O)—, —C(O)N(R₈)—, or —C(O)O—. Preferably,the C group is attached to B via an aliphatic moiety within B.

In one embodiment, the linker B is between 1-24 atoms, preferably 4-24atoms, preferably 4-18 atoms, more preferably 4-12 atoms, and mostpreferably about 4-10 atoms.

In a preferred embodiment, B is selected from straight chain C₁-C₁₀alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, alkoxyC₁-C₁₀alkylamino, C₁-C₁₀alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC ₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀alkenyl,heteroarylC₂-C₁₀alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl,heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀alkynyl,heteroaryloxyC₁-C₁₀alkylamino, heteroaryloxyC₁-C₁₀alkoxy. In the mostpreferred embodiments, the C group is attached to B via an aliphaticmoiety carbon chain, an aryl group or a heteroaryl group within B.

In a particularly preferred embodiment, B is an aryl, heteroaryl,C₁-C₁₀-alkylaryl, C₁-C₁₀-alkylheteroaryl group,C₁-C₁₀-alkylheterocyclylaryl, C₁-C₁₀-alkylheterocyclylheteroaryl,C₁-C₁₀-alkylheterocyclylaryl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylheterocyclylheteroaryl-C₁-C₁₀-alkyl group.

It is understood that alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl and the like can be further substituted.

In certain embodiments of the compounds of Formulas I-XIX, B is selectedfrom the group:

In the foregoing formulas, d and e are independently 0, 1, 2, 3, 4, 5,6, 7 or 8; and R₁₀₀ is hydrogen or a group selected from C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, and C₃-C₈ cycloalkyl. Preferred alkylgroups are —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)CH₃, —C(CH₃)₂CH₃,—C(CH₃)₃. Preferably, R₁₀₀ is hydrogen or methyl.

Representative compounds according to the invention are those selectedfrom the Table A below or the geometric isomers, enantiomers,diastereomers, racemates, pharmaceutically acceptable salts, andprodrugs thereof. It is to be understood that in any structure in TableA in which a nitrogen atom is represented with an open valence, thatvalence is occupied by a hydrogen atom.

TABLE A Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

The invention further provides methods for the prevention or treatmentof diseases or conditions involving aberrant proliferation,differentiation or survival of cells. In one embodiment, the inventionfurther provides for the use of one or more compounds of the inventionin the manufacture of a medicament for halting or decreasing diseasesinvolving aberrant proliferation, differentiation, or survival of cells.In preferred embodiments, the disease is cancer. In one embodiment, theinvention relates to a method of treating cancer in a subject in need oftreatment comprising administering to said subject a therapeuticallyeffective amount of a compound of the invention.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma, renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the invention, thepresent invention provides for the use of one or more compounds of theinvention in the manufacture of a medicament for the treatment ofcancer.

In one embodiment, the present invention includes the use of one or morecompounds of the invention in the manufacture of a medicament thatprevents further aberrant proliferation, differentiation, or survival ofcells. For example, compounds of the invention may be useful inpreventing tumors from increasing in size or from reaching a metastaticstate. The subject compounds may be administered to halt the progressionor advancement of cancer or to induce tumor apoptosis or to inhibittumor angiogenesis. In addition, the instant invention includes use ofthe subject compounds to prevent a recurrence of cancer.

This invention further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

“Combination therapy” includes the administration of the subjectcompounds in further combination with other biologically activeingredients (such as, but not limited to, a second and differentantineoplastic agent) and non-drug therapies (such as, but not limitedto, surgery or radiation treatment). For instance, the compounds of theinvention can be used in combination with other pharmaceutically activecompounds, preferably compounds that are able to enhance the effect ofthe compounds of the invention. The compounds of the invention can beadministered simultaneously (as a single preparation or separatepreparation) or sequentially to the other drug therapy. In general, acombination therapy envisions administration of two or more drugs duringa single cycle or course of therapy.

In one aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate protein kinases involved in various disease states. Examples ofsuch kinases may include, but are not limited to: serine/threoninespecific kinases, receptor tyrosine specific kinases and non-receptortyrosine specific kinases. Serine/threonine kinases include mitogenactivated protein kinases (MAPK), meiosis specific kinase (MEK), RAF andaurora kinase. Examples of receptor kinase families include epidermalgrowth factor receptor (EGFR) (e.g. HER2/neu, HER3, HER4, ErbB, ErbB2,ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor(e.g. FGF-R1,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R);hepatocyte growth/scatter factor receptor (HGFR) (e.g, MET, RON, SEA,SEX); insulin receptor (e.g. IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK,EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (e.g.Mer/Nyk, Rse); RET; and platelet-derived growth factor receptor (PDGFR)(e.g. PDGFα-R, PDGβ-R, CSF1-R/FMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1,FLT3/FLK2/STK-1). Non-receptor tyrosine kinase families include, but arenot limited to, BCR-ABL (e.g. p43^(abl), ARG); BTK (e.g. ITK/EMT, TEC);CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate non-kinase biological targets or processes. Such targetsinclude histone deacetylases (HDAC), DNA methyltransferase (DNMT), heatshock proteins (e.g. HSP90), and proteosomes.

In a preferred embodiment, subject compounds may be combined withantineoplastic agents (e.g. small molecules, monoclonal antibodies,antisense RNA, and fusion proteins) that inhibit one or more biologicaltargets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent,Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak,Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322,Obatodax, ABT737 and AEE788. Such combinations may enhance therapeuticefficacy over efficacy achieved by any of the agents alone and mayprevent or delay the appearance of resistant mutational variants.

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents encompass a wide range of therapeutic treatmentsin the field of oncology. These agents are administered at variousstages of the disease for the purposes of shrinking tumors, destroyingremaining cancer cells left over after surgery, inducing remission,maintaining remission and/or alleviating symptoms relating to the canceror its treatment. Examples of such agents include, but are not limitedto, alkylating agents such as mustard gas derivatives (Mechlorethamine,cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines(thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazinesand Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide),Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide andmetal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloidssuch as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxeland Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine andVinorelbine), and Camptothecan analogs (Irinotecan and Topotecan);anti-tumor antibiotics such as Chromomycins (Dactinomycin andPlicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibioticssuch as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such asfolic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed,Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists(6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine,Nelarabine and Pentostatin); topoisomerase inhibitors such astopoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase IIinhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide);monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab,Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor(Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubuleagents (Estramustine); and retinoids (Bexarotene, Isotretinoin,Tretinoin (ATRA).

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemoprotective agent.Chemoprotective agents act to protect the body or minimize the sideeffects of chemotherapy. Examples of such agents include, but are notlimited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administeredin combination with radiation therapy. Radiation is commonly deliveredinternally (implantation of radioactive material near cancer site) orexternally from a machine that employs photon (x-ray or gamma-ray) orparticle radiation. Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

It will be appreciated that compounds of the invention can be used incombination with an immunotherapeutic agent. One form of immunotherapyis the generation of an active systemic tumor-specific immune responseof host origin by administering a vaccine composition at a site distantfrom the tumor. Various types of vaccines have been proposed, includingisolated tumor-antigen vaccines and anti-idiotype vaccines. Anotherapproach is to use tumor cells from the subject to be treated, or aderivative of such cells (reviewed by Schirrmacher et al. (1995) J.Cancer Res. Clin. Oncol. 121:487). In U.S. Pat. No. 5,484,596, Hanna Jr.et al. claim a method for treating a resectable carcinoma to preventrecurrence or metastases, comprising surgically removing the tumor,dispersing the cells with collagenase, irradiating the cells, andvaccinating the patient with at least three consecutive doses of about10⁷ cells.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more adjunctivetherapeutic agents. Examples of suitable agents for adjunctive therapyinclude a 5HT₁ agonist, such as a triptan (e.g. sumatriptan ornaratriptan); an adenosine A1 agonist; an EP ligand; an NMDA modulator,such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g. an NK₁ antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentinand related compounds; a tricyclic antidepressant (e.g. amitryptilline);a neuron stabilising antiepileptic drug; a mono-aminergic uptakeinhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOSinhibitor; an inhibitor of the release, or action, of tumour necrosisfactor .alpha.; an antibody therapy, such as a monoclonal antibodytherapy; an antiviral agent, such as a nucleoside inhibitor (e.g.lamivudine) or an immune system modulator (e.g. interferon); an opioidanalgesic; a local anaesthetic; a stimulant, including caffeine; anH₂-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g.omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; anantiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine,phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine);an antitussive (e.g. codeine, hydrocodone, carmiphen, carbetapentane, ordextramethorphan); a diuretic; or a sedating or non-sedatingantihistamine.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutralendopeptidases collectively capable of degrading essentially all matrixcomponents. Over 20 MMP modulating agents are in pharmaceutical develop,almost half of which are indicated for cancer. The University of Torontoresearchers have reported that HDACs regulate MMP expression andactivity in 3T3 cells. In particular, inhibition of HDAC by trichostatinA (TSA), which has been shown to prevent tumorigenesis and metastasis,decreases mRNA as well as zymographic activity of gelatinase A (MMP2;Type IV collagenase), a matrix metalloproteinase, which is itself,implicated in tumorigenesis and metastasis (Ailenberg M., Silverman M.,Biochem Biophys Res Commun. 2002, 298:110-115). Another recent articlethat discusses the relationship of HDAC and MMPs can be found in YoungD. A., et al., Arthritis Research & Therapy, 2005, 7: 503. Furthermore,the commonality between HDAC and MMPs inhibitors is their zinc-bindingfunctionality. Therefore, in one aspect of the invention, compounds ofthe invention can be used as MMP inhibitors and may be of use in thetreatment of disorders relating to or associated with dysregulation ofMMP. The overexpression and activation of MMPs are known to inducetissue destruction and are also associated with a number of specificdiseases including rheumatoid arthritis, periodontal disease, cancer andatherosclerosis.

The compounds may also be used in the treatment of a disorder involving,relating to or, associated with dysregulation of histone deacetylase(HDAC). There are a number of disorders that have been implicated by orknown to be mediated at least in part by HDAC activity, where HDACactivity is known to play a role in triggering disease onset, or whosesymptoms are known or have been shown to be alleviated by HDACinhibitors. Disorders of this type that would be expected to be amenableto treatment with the compounds of the invention include the followingbut not limited to: Anti-proliferative disorders (e.g. cancers);Neurodegenerative diseases including Huntington's Disease, Polyglutaminedisease, Parkinson's Disease, Alzheimer's Disease, Seizures,Striatonigral degeneration, Progressive supranuclear palsy, Torsiondystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gillesde la Tourette syndrome, Diffuse Lewy body disease, Progressivesupranuclear palsy, Pick's disease, intracerebral hemorrhage, Primarylateral sclerosis, Spinal muscular atrophy, Amyotrophic lateralsclerosis, Hypertrophic interstitial polyneuropathy, Retinitispigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia,Progressive ataxia and Shy-Drager syndrome; Metabolic diseases includingType 2 diabetes; Degenerative Diseases of the Eye including Glaucoma,Age-related macular degeneration, Rubeotic glaucoma; Inflammatorydiseases and/or Immune system disorders including Rheumatoid Arthritis(RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Hostdisease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease,inflammatory bowel disease Colitis Ulcerosa, Alcoholic hepatitis,Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosingspondylitis, Membranous glomerulopathy, Discogenic pain, Systemic LupusErythematosus; Disease involving angiogenesis including cancer,psoriasis, rheumatoid arthritis; Psychological disorders includingbipolar disease, schizophrenia, mania, depression and dementia;Cardiovascular Diseases including the prevention and treatment ofischemia-related or reperfusion-related vascular and myocardial tissuedamage, heart failure, restenosis and arteriosclerosis; Fibroticdiseases including liver fibrosis, cystic fibrosis and angiofibroma;Infectious diseases including Fungal infections, such as candidiasis orCandida Albicans, Bacterial infections, Viral infections, such as HerpesSimplex, poliovirus, rhinovirus and coxsackievirus, Protozoalinfections, such as Malaria, Leishmania infection, Trypanosoma bruceiinfection, Toxoplasmosis and coccidlosis and Haematopoietic disordersincluding thalassemia, anemia and sickle cell anemia.

The compounds can also be used in the treatment of a disorder involving,relating to or, associated with dysregulation of mammalian target ofrapamycin (mTOR). mTOR dysregulation has been implicated in or shown tobe involved in a variety of disorders. In certain cases, mTOR activityis involved in triggering disease onset, while in others, symptoms areknown or have been shown to be alleviated by inhibitors of mTORactivity. Disorders of this type that would be expected to be amenableto treatment with the compounds of the invention include but are notlimited to cancers, including breast cancer, prostate cancer, lungcancer, including non-small cell lung cancer and small cell lung cancer;pancreatic cancer, multiple myeloma, brain cancer, includingglioblastoma multiforme, malignant glioma and gliosarcoma; skin cancer,including melanoma; renal cancer, including renal cell carcinoma;gastric cancer, colorectal cancer, colon cancer, lymphoma, leukemia,ovarian cancer, bladder cancer, uterine cancer, endometrial cancer andislet cell carcinoma; restenosis, atherosclerosis, bone disorders,arthritis, diabetic retinopathy, psoriasis, benign prostatichypertrophy, atherosclerosis, inflammation, angiogenesis, immunologicaldisorders, pancreatitis, and kidney disease.

The compounds can also be used in the treatment of a disorder involving,relating to or, associated with dysregulation of PI3 kinase. PI3 kinaseactivity has been implicated in or shown to be involved in a variety ofdisorders. In certain cases, PI3 kinase activity is involved intriggering disease onset, while in others, symptoms are known or havebeen shown to be alleviated by inhibitors of PI3 kinase activity.Disorders of this type that would be expected to be amenable totreatment with the compounds of the invention include but are notlimited to cancers, including leukemia, skin cancer, bladder cancer,breast cancer, uterine cancer, ovarian cancer, prostate cancer, lungcancer, colon cancer, pancreatic cancer, renal cancer, gastric cancerand brain cancer; restenosis, atherosclerosis, bone disorders,arthritis, diabetic retinopathy, psoriasis, benign prostatichypertrophy, atherosclerosis, inflammation, angiogenesis, immunologicaldisorders, pancreatitis and kidney disease.

In one embodiment, compounds of the invention can be used to induce orinhibit apoptosis, a physiological cell death process critical fornormal development and homeostasis. Alterations of apoptotic pathwayscontribute to the pathogenesis of a variety of human diseases. Compoundsof the invention, as modulators of apoptosis, will be useful in thetreatment of a variety of human diseases with aberrations in apoptosisincluding cancer (particularly, but not limited to, follicularlymphomas, carcinomas with p53 mutations, hormone dependent tumors ofthe breast, prostate and ovary, and precancerous lesions such asfamilial adenomatous polyposis), viral infections (including, but notlimited to, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virusand adenovirus), autoimmune diseases (including, but not limited to,systemic lupus, erythematosus, immune mediated glomerulonephritis,rheumatoid arthritis, psoriasis, inflammatory bowel diseases, andautoimmune diabetes mellitus), neurodegenerative disorders (including,but not limited to, Alzheimer's disease, AIDS-related dementia,Parkinson's disease, amyotrophic lateral sclerosis, retinitispigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS,myelodysplastic syndromes, aplastic anemia, ischemic injury associatedmyocardial infarctions, stroke and reperfusion injury, arrhythmia,atherosclerosis, toxin-induced or alcohol induced liver diseases,hematological diseases (including, but not limited to, chronic anemiaand aplastic anemia), degenerative diseases of the musculoskeletalsystem (including, but not limited to, osteoporosis and arthritis),aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis,kidney diseases, and cancer pain.

In one aspect, the invention provides the use of compounds of theinvention for the treatment and/or prevention of immune response orimmune-mediated responses and diseases, such as the prevention ortreatment of rejection following transplantation of synthetic or organicgrafting materials, cells, organs or tissue to replace all or part ofthe function of tissues, such as heart, kidney, liver, bone marrow,skin, cornea, vessels, lung, pancreas, intestine, limb, muscle, nervetissue, duodenum, small-bowel, pancreatic-islet-cell, includingxeno-transplants, etc.; to treat or prevent graft-versus-host disease,autoimmune diseases, such as rheumatoid arthritis, systemic lupuserythematosus, thyroiditis, Hashimoto's thyroiditis, multiple sclerosis,myasthenia gravis, type I diabetes uveitis, juvenile-onset orrecent-onset diabetes mellitus, uveitis, Graves disease, psoriasis,atopic dermatitis, Crohn's disease, ulcerative colitis, vasculitis,auto-antibody mediated diseases, aplastic anemia, Evan's syndrome,autoimmune hemolytic anemia, and the like; and further to treatinfectious diseases causing aberrant immune response and/or activation,such as traumatic or pathogen induced immune disregulation, includingfor example, that which are caused by hepatitis B and C infections, HIV,staphylococcus aureus infection, viral encephalitis, sepsis, parasiticdiseases wherein damage is induced by an inflammatory response (e.g.,leprosy); and to prevent or treat circulatory diseases, such asarteriosclerosis, atherosclerosis, vasculitis, polyarteritis nodosa andmyocarditis. In addition, the present invention may be used toprevent/suppress an immune response associated with a gene therapytreatment, such as the introduction of foreign genes into autologouscells and expression of the encoded product. Thus in one embodiment, theinvention relates to a method of treating an immune response disease ordisorder or an immune-mediated response or disorder in a subject in needof treatment comprising administering to said subject a therapeuticallyeffective amount of a compound of the invention.

In one aspect, the invention provides the use of compounds of theinvention in the treatment of a variety of neurodegenerative diseases, anon-exhaustive list of which includes: I. Disorders characterized byprogressive dementia in the absence of other prominent neurologic signs,such as Alzheimer's disease; Senile dementia of the Alzheimer type; andPick's disease (lobar atrophy); II. Syndromes combining progressivedementia with other prominent neurologic abnormalities such as A)syndromes appearing mainly in adults (e.g., Huntington's disease,Multiple system atrophy combining dementia with ataxia and/ormanifestations of Parkinson's disease, Progressive supranuclear palsy(Steel-Richardson-Olszewski), diffuse Lewy body disease, andcorticodentatonigral degeneration); and B) syndromes appearing mainly inchildren or young adults (e.g., Hallervorden-Spatz disease andprogressive familial myoclonic epilepsy); III. Syndromes of graduallydeveloping abnormalities of posture and movement such as paralysisagitans (Parkinson's disease), striatonigral degeneration, progressivesupranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorumdeformans), spasmodic torticollis and other dyskinesis, familial tremor,and Gilles de la Tourette syndrome; IV. Syndromes of progressive ataxiasuch as cerebellar degenerations (e.g., cerebellar cortical degenerationand olivopontocerebellar atrophy (OPCA)); and spinocerebellardegeneration (Friedreich's atazia and related disorders); V. Syndrome ofcentral autonomic nervous system failure (Shy-Drager syndrome); VI.Syndromes of muscular weakness and wasting without sensory changes(motorneuron disease such as amyotrophic lateral sclerosis, spinalmuscular atrophy (e.g., infantile spinal muscular atrophy(Werdnig-Hoffman), juvenile spinal muscular atrophy(Wohlfart-Kugelberg-Welander) and other forms of familial spinalmuscular atrophy), primary lateral sclerosis, and hereditary spasticparaplegia; VII. Syndromes combining muscular weakness and wasting withsensory changes (progressive neural muscular atrophy; chronic familialpolyneuropathies) such as peroneal muscular atrophy(Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy(Dejerine-Sottas), and miscellaneous forms of chronic progressiveneuropathy; VIII Syndromes of progressive visual loss such as pigmentarydegeneration of the retina (retinitis pigmentosa), and hereditary opticatrophy (Leber's disease). Furthermore, compounds of the invention canbe implicated in chromatin remodeling.

The invention encompasses pharmaceutical compositions comprisingpharmaceutically acceptable salts of the compounds of the invention asdescribed above. The invention also encompasses solvates of thecompounds of the invention and pharmaceutical compositions comprisingsuch solvates, such as hydrates, methanolates or ethanolates. The term“solvate” refers to a solid, preferably crystalline, form of a compoundwhich includes the presence of solvent molecules within the crystallattice. A solvate of a compound comprising a given solvent is typicallyprepared by crystallization of the compound from that solvent. Solvatescan include a variety of solvents, including water, methanol andethanol. The term “hydrate” refers to a solvate in which the solvent iswater, and includes, but is not limited to, hemihydrate, monohydrate,dihydrate, trihydrate and the like. The invention further encompassespharmaceutical compositions comprising any solid or liquid physical formof the compound of the invention, including crystalline and crystallinesolvate forms. For example, the compounds can be in a crystalline form,in amorphous form, and have any particle size. The particles may bemicronized, or may be agglomerated, particulate granules, powders, oils,oily suspensions or any other form of solid or liquid physical form.

The compounds of the invention, and derivatives, fragments, analogs,homologs, pharmaceutically acceptable salts or solvates thereof can beincorporated into pharmaceutical compositions suitable foradministration, together with a pharmaceutically acceptable carrier orexcipient. Such compositions typically comprise a therapeuticallyeffective amount of any of the compounds above, and a pharmaceuticallyacceptable carrier. Preferably, the effective amount when treatingcancer is an amount effective to selectively induce terminaldifferentiation of suitable neoplastic cells and less than an amountwhich causes toxicity in a patient.

Compounds of the invention may be administered by any suitable means,including, without limitation, parenteral, intravenous, intramuscular,subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary,transdermal, topical, vaginal, rectal, and transmucosal administrationsor the like. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Pharmaceutical preparations include a solid, semisolid orliquid preparation (tablet, pellet, troche, capsule, suppository, cream,ointment, aerosol, powder, liquid, emulsion, suspension, syrup,injection etc.) containing a compound of the invention as an activeingredient, which is suitable for selected mode of administration. Inone embodiment, the pharmaceutical compositions are administered orally,and are thus formulated in a form suitable for oral administration,i.e., as a solid or a liquid preparation. Suitable solid oralformulations include tablets, capsules, pills, granules, pellets,sachets and effervescent, powders, and the like. Suitable liquid oralformulations include solutions, suspensions, dispersions, emulsions,oils and the like. In one embodiment of the present invention, thecomposition is formulated in a capsule. In accordance with thisembodiment, the compositions of the present invention comprise inaddition to the active compound and the inert carrier or diluent, a hardgelatin capsule.

Any inert excipient that is commonly used as a carrier or diluent may beused in the formulations of the present invention, such as for example,a gum, a starch, a sugar, a cellulosic material, an acrylate, ormixtures thereof. A preferred diluent is microcrystalline cellulose. Thecompositions may further comprise a disintegrating agent (e.g.,croscarmellose sodium) and a lubricant (e.g., magnesium stearate), andmay additionally comprise one or more additives selected from a binder,a buffer, a protease inhibitor, a surfactant, a solubilizing agent, aplasticizer, an emulsifier, a stabilizing agent, a viscosity increasingagent, a sweetener, a film forming agent, or any combination thereof.Furthermore, the compositions of the present invention may be in theform of controlled release or immediate release formulations.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

In addition, the compositions may further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), buffers (e.g., tris-HCI., acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol), a glidant(e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosityincreasing agents (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citricacid), flavoring agents (e.g., peppermint, methyl salicylate, or orangeflavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens),lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol,sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat No.4,522,811.

It is especially advantageous to formulate oral compositions in dosageunit form for ease of administration and uniformity of dosage. Dosageunit form as used herein refers to physically discrete units suited asunitary dosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Daily administration may be repeated continuously for a period ofseveral days to several years. Oral treatment may continue for betweenone week and the life of the patient. Preferably the administration maytake place for five consecutive days after which time the patient can beevaluated to determine if further administration is required. Theadministration can be continuous or intermittent, e.g., treatment for anumber of consecutive days followed by a rest period. The compounds ofthe present invention may be administered intravenously on the first dayof treatment, with oral administration on the second day and allconsecutive days thereafter.

The preparation of pharmaceutical compositions that contain an activecomponent is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than anamount that would cause toxicity in the patient. In certain embodiments,the amount of the compound that is administered to the patient is lessthan the amount that causes a concentration of the compound in thepatient's plasma to equal or exceed the toxic level of the compound.Preferably, the concentration of the compound in the patient's plasma ismaintained at about 10 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 25 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 50 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 100 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 1000 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 2500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 5000 nM. Theoptimal amount of the compound that should be administered to thepatient in the practice of the present invention will depend on theparticular compound used and the type of cancer being treated.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” or “aliphatic” is non-aromatic moiety that may besaturated (e.g. single bond) or contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic, contain carbon, hydrogen or,optionally, one or more heteroatoms and may be substituted orunsubstituted. An aliphatic group, when used as a linker, preferablycontains between about 1 and about 24 atoms, more preferably betweenabout 4 to about 24 atoms, more preferably between about 4-12 atoms,more typically between about 4 and about 8 atoms. An aliphatic group,when used as a substituent, preferably contains between about 1 andabout 24 atoms, more preferably between about 1 to about 10 atoms, morepreferably between about 1-8 atoms, more typically between about 1 andabout 6 atoms. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl groups described herein.

The term “substituted carbonyl” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain asubstituted carbonyl include aldehydes, ketones, carboxylic acids,amides, esters, anhydrides, etc. The term “carbonyl moiety” refers togroups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide).

The term “acyl” refers to hydrogen, alkyl, partially saturated or fullysaturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” embraces linear or branched radicals having one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkyl radicals are “lower alkyl” radicals havingone to about ten carbon atoms. Most preferred are lower alkyl radicalshaving one to about eight carbon atoms. Examples of such radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkenylradicals are “lower alkenyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyland 4-methylbutenyl. The terms “alkenyl”, and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” embraces linear or branched radicals having at leastone carbon-carbon triple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl,1-butyne, 2-butynyl and 1-pentynyl.

The term “cycloalkyl” embraces saturated carbocyclic radicals havingthree to about twelve carbon atoms. The term “cycloalkyl” embracessaturated carbocyclic radicals having three to about twelve carbonatoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to about eight carbon atoms. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkenyl” embraces partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxyradicals attached to the alkyl radical, that is, to form monoalkoxyalkyland dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”embrace saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” embraces unsaturated heterocyclyl radicals.Examples of heteroaryl radicals include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” embraces heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radicals.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkylthio radicals have alkyl radicals are “loweralkylthio” radicals having one to about ten carbon atoms. Most preferredare alkylthio radicals having lower alkyl radicals of one to about eightcarbon atoms. Examples of such lower alkylthio radicals are methylthio,ethylthio, propylthio, butylthio and hexylthio.

The terms “aralkyl” or “arylalkyl” embrace aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” embraces aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” embrace aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” embraces alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred aminoalkyl radicals are “lower aminoalkyl”that have alkyl radicals having one to about ten carbon atoms. Mostpreferred are aminoalkyl radicals having lower alkyl radicals having oneto eight carbon atoms. Examples of such radicals include aminomethyl,aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “linker” means an organic moiety that connects two parts of acompound. Linkers typically comprise a direct bond or an atom such asoxygen or sulfur, a unit such as NR₈, C(O), C(O)NH, SO, SO₂, SO₂NH or achain of atoms, such as substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl,heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl,alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl,alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl,alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl,alkenylheteroarylalkyl, alkenylheteroarylalkenyl,alkenylheteroarylalkynyl, alkynylheteroarylalkyl,alkynylheteroarylalkenyl, alkynylheteroarylalkynyl,alkylheterocyclylalkyl, alkylheterocyclylalkenyl,alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl,alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl,alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl,alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or moremethylenes can be interrupted or terminated by O, S, S(O), SO₂, N(R₈),C(O), substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclic; where R₈ ishydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment,the linker B is between 1-24 atoms, preferably 4-24 atoms, preferably4-18 atoms, more preferably 4-12 atoms, and most preferably about 4-10atoms. In some embodiments, the linker is a C(O)NH(alkyl) chain or analkoxy chain. It is to be understood that an asymmetric linker, such asalkylaryl, can connect two structurally distinct moieties in either ofits two possible orientations.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties are defined and referred to throughoutcan be univalent chemical moieties (e.g., alkyl, aryl, etc.) ormultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy“, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

As used herein, the term “aberrant proliferation” refers to abnormalcell growth.

The phrase “adjunctive therapy” encompasses treatment of a subject withagents that reduce or avoid side effects associated with the combinationtherapy of the present invention, including, but not limited to, thoseagents, for example, that reduce the toxic effect of anticancer drugs,e.g., bone resorption inhibitors, cardioprotective agents; prevent orreduce the incidence of nausea and vomiting associated withchemotherapy, radiotherapy or operation; or reduce the incidence ofinfection associated with the administration of myelosuppressiveanticancer drugs.

The term “angiogenesis,” as used herein, refers to the formation ofblood vessels. Specifically, angiogenesis is a multi-step process inwhich endothelial cells focally degrade and invade through their ownbasement membrane, migrate through interstitial stroma toward anangiogenic stimulus, proliferate proximal to the migrating tip, organizeinto blood vessels, and reattach to newly synthesized basement membrane(see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)).Anti-angiogenic agents interfere with this process. Examples of agentsthat interfere with several of these steps include thrombospondin-1,angiostatin, endostatin, interferon alpha and compounds such as matrixmetalloproteinase (MMP) inhibitors that block the actions of enzymesthat clear and create paths for newly forming blood vessels to follow;compounds, such as .alpha.v.beta.3 inhibitors, that interfere withmolecules that blood vessel cells use to bridge between a parent bloodvessel and a tumor; agents, such as specific COX-2 inhibitors, thatprevent the growth of cells that form new blood vessels; andprotein-based compounds that simultaneously interfere with several ofthese targets.

The term “apoptosis” as used herein refers to programmed cell death assignaled by the nuclei in normally functioning human and animal cellswhen age or state of cell health and condition dictates. An “apoptosisinducing agent” triggers the process of programmed cell death.

The term “cancer” as used herein denotes a class of diseases ordisorders characterized by uncontrolled division of cells and theability of these cells to invade other tissues, either by direct growthinto adjacent tissue through invasion or by implantation into distantsites by metastasis.

The term “compound” is defined herein to include pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, enantiomers,diastereoisomers, racemates and the like of the compounds having aformula as set forth herein.

The term “device” refers to any appliance, usually mechanical orelectrical, designed to perform a particular function.

As used herein, the term “dysplasia” refers to abnormal cell growth, andtypically refers to the earliest form of pre-cancerous lesionrecognizable in a biopsy by a pathologist.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about, e.g. a change in the rate of cell proliferationand/or state of differentiation and/or rate of survival of a cell toclinically acceptable standards. This amount may further relieve to someextent one or more of the symptoms of a neoplasia disorder, including,but is not limited to: 1) reduction in the number of cancer cells; 2)reduction in tumor size; 3) inhibition (i.e., slowing to some extent,preferably stopping) of cancer cell infiltration into peripheral organs;4) inhibition (i.e., slowing to some extent, preferably stopping) oftumor metastasis; 5) inhibition, to some extent, of tumor growth; 6)relieving or reducing to some extent one or more of the symptomsassociated with the disorder; and/or 7) relieving or reducing the sideeffects associated with the administration of anticancer agents.

The term “hyperplasia,” as used herein, refers to excessive celldivision or growth.

The phrase an “immunotherapeutic agent” refers to agents used totransfer the immunity of an immune donor, e.g., another person or ananimal, to a host by inoculation. The term embraces the use of serum orgamma globulin containing performed antibodies produced by anotherindividual or an animal; nonspecific systemic stimulation; adjuvants;active specific immunotherapy; and adoptive immunotherapy. Adoptiveimmunotherapy refers to the treatment of a disease by therapy or agentsthat include host inoculation of sensitized lymphocytes, transferfactor, immune RNA, or antibodies in serum or gamma globulin.

The term “inhibition,” in the context of neoplasia, tumor growth ortumor cell growth, may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention or chemoprevention.

The term “metastasis,” as used herein, refers to the migration of cancercells from the original tumor site through the blood and lymph vesselsto produce cancers in other tissues. Metastasis also is the term usedfor a secondary cancer growing at a distant site.

The term “neoplasm,” as used herein, refers to an abnormal mass oftissue that results from excessive cell division. Neoplasms may bebenign (not cancerous), or malignant (cancerous) and may also be calleda tumor. The term “neoplasia” is the pathological process that resultsin tumor formation.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “proliferation” refers to cells undergoing mitosis.

The phrase “PI3 kinase related disease or disorder” refers to a diseaseor disorder characterized by inappropriate phosphoinositide-3-kinaseactivity or over-activity of the phosphoinositide-3-kinase.Inappropriate activity refers to either; (i) PI3 kinase expression incells which normally do not express PI3 kinase; (ii) increased PI3kinase expression leading to unwanted cell proliferation,differentiation and/or growth; or, (iii) decreased PI3 kinase expressionleading to unwanted reductions in cell proliferation, differentiationand/or growth. Over-activity of PI3 kinase refers to eitheramplification of the gene encoding a particular PI3 kinase or productionof a level of PI3 kinase activity which can correlate with a cellproliferation, differentiation and/or growth disorder (that is, as thelevel of the PI3 kinase increases, the severity of one or more of thesymptoms of the cellular disorder increases).

The phrase a “radio therapeutic agent” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.

The term “recurrence” as used herein refers to the return of cancerafter a period of remission. This may be due to incomplete removal ofcells from the initial cancer and may occur locally (the same site ofinitial cancer), regionally (in vicinity of initial cancer, possibly inthe lymph nodes or tissue), and/or distally as a result of metastasis.

The term “treatment” refers to any process, action, application,therapy, or the like, wherein a mammal, including a human being, issubject to medical aid with the object of improving the mammal'scondition, directly or indirectly.

The term “vaccine” includes agents that induce the patient's immunesystem to mount an immune response against the tumor by attacking cellsthat express tumor associated antigens (Teas).

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid or inorganic acid. Examples of pharmaceuticallyacceptable nontoxic acid addition salts include, but are not limited to,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid lactobionic acid or malonic acid or byusing other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

As used herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Preferredexamples of such carriers or diluents include, but are not limited to,water, saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers and/or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha- (α), beta- (β) and gamma- (γ)cyclodextrins; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols such as propylene glycol; esters suchas ethyl oleate and ethyl laurate; agar; buffering agents such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not limiting ofthe scope of the invention.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Preparation ofN-hydroxy-5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)pentanamide(Compound 3)

Step 1a: 1-(Methylthioperoxy)piperazine trifluoroacetic acid salt(Compound 0103)

A mixture of compound 0101 (10.0 g, 54 mmol), methanesulfonyl chloride(6.5 g, 57 mmol) and triethylamine in CH₂Cl₂ (50 mL) was stirred atreflux overnight. The reaction was cooled to room temperature andfiltered. The filtrate was concentrated to give compound 0102 which wasused to the next step without further purification. A mixture ofcompound 0102 and trifluoroacetic acid (15 mL) in CH₂Cl₂ (100 mL) wasstirred at room temperature for 3 h. The reaction was filtered and thefiltrate was concentrated to give the title compound 0103 (9.7 g, 66%)as a white solid. LCMS: 165 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.99 (s,3H), 3.21 (m, 4H), 3.33 (m, 4H), 8.95 (br s, 2H).

Step 1b: 4-Bromo-1H-indazole (Compound 0106-3)

To a solution of 3-bromo-2-methyl aniline (0104) (0.50 g, 2.69 mmol) inchloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). Themixture was cooled with ice-water bath and then acetic anhydride (0.50mL, 5.37 mmol) was added to it. Ice-water bath was then removed and theresulting mixture was stirred at room temperature for 10 minutes afterwhich time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol).The mixture was then heated under reflux for 18 hours. The reactionmixture was allowed to cool, and was partitioned between chloroform(3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). Thecombined organic extracts were washed with brine (10 mL), dried overNa₂SO₄, filtered and evaporated to give a crude product which waspurified by column chromatography (ethyl acetate in petroleum ether, 10%v/v) to give 1-(4-bromoindrazol-1-y1)-ethanone (0105) as an orange solid(0.31 g, 49%), and 4-bromo-1H-indazole (0106-3) as a pale orange solid(0.21 g, 40%). Compound 0105: LCMS: 239 [M+1]⁺; ¹H NMR (400 Hz, CDCl₃) δ2.80 (s, 3H), 7.41 (t, J=6.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 8.15 (s,1H), 8.40 (d, J=6.8 Hz, 1H). Compound 0106: LCMS: 197 [M+1]⁺; ¹H NMR(400 Hz, CDCl₃) δ 7.25 (t, J=6.0 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.46(d, J=6.8 Hz, 1H), 8.12 (s, 1H).

To a solution of compound 0105 (0.30g, 1.29 mmol) in methanol (5.0 mL)was added 6 N aqueous HCl (3.0 mL). The mixture was stirred at roomtemperature for 7 h. Methanol was evaporated and the mixture partitionedbetween EtOAc (2×50 mL) and water (5.0 mL). The combined organic layerswere washed with brine (5.0 mL), dried over Na₂SO₄, filtered andevaporated to give 4-bromo-1H-indazole (0106-3) (0.24 g, 94%).

Step 1c: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(Compound 0107-3)

To a stirred solution of compound 0106 (500 mg, 2.54 mmol) andbis(pinacolato)diboron (968 mg, 3.81 mmol) in DMSO (20 mL) was addedpotassium acetate (747 mg, 7.61 mmol) and PdCl₂(dppf)₂ (3 mol %, 62 mg,0.076 mmol). The mixture was degassed with argon and heated at 80° C.for 40 hours. The reaction mixture was allowed to cool and partitionedbetween water (50 mL) and ether (3×50 mL). The combined organic layerswere separated, washed with brine (50 mL), dried over MgSO₄, filteredand evaporated to give crude material which was purified by columnchromatography (ethyl acetate in petroleum ether, 20% v/v) to givecompound 0107-3 as an off-white solid (370 mg, 60%): LCMS: 245 [M+1]⁺;¹H NMR (400 Hz, CDCl₃) δ 1.41 (s, 12H), 7.40 (dd, J=6.8 Hz, 8.4 Hz, 1H),7.62 (d, J=8.8 Hz, 1H), 7.90 (d, J=6.8 Hz, 1H), 8.50 (s, 1H).

Step 1d: Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (Compound 0109)

A mixture of methyl 3-amino-2-thiophenecarboxylate (0108) (13.48 g,85.85 mmol) and urea (29.75 g, 0.43 mol) was heated at 190° C. for 2 h.The hot reaction mixture was poured into sodium hydroxide solution andinsoluble material was removed by filtration. The mixture was thenacidified by 2 N HCl solution. The resulting solid was collected byfiltration, dried to give title compound 0109 (9.62 g, 67%) as a whitesolid: LCMS: 169 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 6.92 (d, J=4.0 Hz,1H), 8.04 (d, J=4.0 Hz, 1H), 11.19 (d, J=14.0 Hz, 1H), 11.60 (s, 1H).

Step 1e: 2,4-Dichlorothieno[3,2-d]pyrimidine (Compound 0110)

A mixture of compound 0109 (9.49 g, 56.49 mmol) and phosphorousoxychloride (150 mL) was heated at reflux for 10 h. The solvent was thenremoved and the residue was poured onto ice/water with vigorous stirringto give title compound 0110 (8.62 g, 74%) as a white solid: LCMS: 205[M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.48 (d, J=5.6 Hz, 1H), 8.05 (d,J=5.6 Hz , 1H).

Step 1f: 4-(2-Chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (Compound0111)

A mixture of compound 0110 (8.68 g, 42.34 mmol) and morpholine (8.11 mL,93.15 mmol) in methanol (150 mL) was stirred at room temperature for 1h. The reaction mixture was then filtered, washed with water (50 mL×3)and methanol (50 mL×1) to give the title compound 0111 (11.04 g, 100%)as a white solid: LCMS: 256 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 3.76(t, J=4.8 Hz, 4H), 3.91 (t, J=4.8 Hz, 4H), 7.41 (d, J=5.6 Hz, 1H), 8.31(d, J=5.6 Hz, 1H).

Step 1g: 2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde(Compound 0112)

To a suspension of compound 0111 (1.75 g, 6.85 mmol) in drytetrahydrofuran (40 mL) at −78° C. was added a 2.0 M solution of LDA inTHF/hexane(20.55 mL, 41.1 mmol). After stirring for 1 h, dryN,N-dimethylformamide (3.2 mL, 41.1 mmol) was added. The reactionmixture was stirred for 1 h at −78° C. and then warmed slowly to roomtemperature. After a further stir for 10 h at room temperature, thereaction mixture was poured onto NH₄Cl saturated solution, extractedwith ethyl acetate (100 mL×3), dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to leave a residue which was washed with ethylacetate (10 mL×2) to give the title compound 0112 (0.66 g, 35%) as ayellow solid: LCMS: 284 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ3.76 (t,J=4.8 Hz, 4H), 4.10 (t, J=4.8 Hz, 4H), 8.29 (s, 1H), 10.21 (s, 1H).

Step 1h:4-(2-Chloro-6-((4-(methylthioperoxy)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine(Compound 0113)

A mixture of compound 0112 (1.10 g, 3.89 mmol), 0103 (2.20 g, 7.78mmol), triethylamine (471 mg, 4.7 mmol) and titanium tetraisopropanolate(1.30 g, 4.67 mmol) in chloroform (30 ml) was stirred at refluxovernight. The solvent was then removed, and 1,2-dichloroethane (40 mL)and sodium cyanborohydride (368 mg, 5.84 mmol) were added. The reactionmixture was then stirred at room temperature for 12 h. The reaction wasconcentrated and the resulting solid was recrystallized with ethanol togive the title compound 0113 (800 mg, 48%) as a yellow solid: LCMS: 432[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 2.57 (t, J=4.4 Hz, 4H), 2.89 (s,3H), 3.13 (t, J=4.4 Hz, 4H), 3.74 (t, J=5.2 Hz, 4H), 3.88 (t, J=5.2 Hz,4H), 3.91 (s, 2H), 7.31 (s, 1H).

Step 1i:4-(2-Chloro-6-((4-(methylthioperoxy)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine(Compound 0114)

A mixture of compound 0113 (800 mg, 1.86 mmol), 0107-3 (500 mg, 2.04mmol), sodium hydrogen carbonate (470 mg, 5.58 mmol) andbis(triphenylphosphine)palladium(0)chloride (80 mg, 0.093 mmol) intoluene (20 mL), ethanol (12 mL) and water (5.6 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was partitioned between dichloromethane and water. Theorganic layer was separated and washed with brine, dried over magnesiumsulfate, filtered and evaporated. The resulting residue was purified bycolumn chromatography (silica gel, dichloromethane, 2%, v/v, to givetitle compound 0114 (350 mg, 37%) as a white solid. mp 148-149° C. LCMS:514 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 2.70 (t, J=4.4 Hz, 4H), 2.81 (s,3H), 3.13 (t, J=4.4 Hz, 4H), 3.92 (m, 6H), 4.09 (t, J=5.6 Hz, 4H), 7.41(s, 1H), 7.50 (m, 1H), 7.59 (d, J=8.4 Hz, 1H), 8.28 (d, J=6.8 Hz, 1H),9.00 (s, 1H), 10.32 (br s, 1H).

Step 1j: Ethyl5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)pentanoate(Compound 0116-3) and ethyl5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)pentanoate(Compound 0115-3)

A mixture of compound 0114 (370 mg, 0.72 mmol), ethyl 5-bromopentanoate(181 mg, 0.87 mmol) and potassium carbonate (199 mg, 1.44 mmol) inacetonitrile (50 mL) was refluxed for 58 hours. Solvent was removed andthe residue was partitioned between dichloromethane and water. Theorganic layer was separated and washed with brine, dried over magnesiumsulfate, filtered and evaporated to give a crude product which waspurified by prep-HPLC to give the title compound 0115-3 (80 mg, 17%) and0116-3 (60 mg, 13%).

Compound 0115-3: a white solid; LCMS: 642 [M+1]⁺; ¹H NMR (400 MHz,CDCl₃): δ 1.15 (t, J=7.2 Hz, 3H), 1.61 (m, 2H), 1.94 (m, 2H), 2.26 (t,J=7.2 Hz, 2H), 2.62 (t, J=4.4 Hz, 4H), 2.74 (s, 3H), 3.23 (t, J=4.4 Hz,4H), 3.84 (m, 6H), 4.01 (m, 6H), 4.38 (t, J=6.8 Hz, 2H), 7.33 (s, 1H),7.42 (m, 2H), 8.17 (m, 1H), 8.81 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ172.2, 161.6, 159.5, 157.1, 147.8, 139.3, 133.7, 131.2, 125.0, 123.0,121.4, 120.8, 112.1, 109.7, 65.8 (2C), 59.3, 56.3, 51.4, 47.5 (2C), 45.6(2C), 44.8 (2C), 33.5, 32.8, 28.6, 21.2, 13.2.

Compound 0116-3: a white solid; LCMS: 642 [M+1]⁺; ¹H NMR (400 MHz,CDCl₃): δ 1.15 (t, J=7.2 Hz, 3H), 1.60 (m, 2H), 2.06 (m, 2H), 2.29 (t,J=7.2 Hz, 2H), 2.63 (s, 4H), 2.74 (s, 3H), 3.24 (s, 4H), 3.84 (m, 6H),4.04 (m, 6H), 4.43 (t, J=6.8 Hz, 2H), 7.33 (m, 2H), 7.74 (d, J=8.4 Hz,1H), 8.19 (d, J=6.8 Hz, 1H), 8.82 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ172.1, 161.5, 159.5, 156.9, 148.8, 147.4, 130.0, 124.6, 123.1, 122.2,119.0, 118.8, 112.0, 65.8 (2C), 59.4, 56.3, 52.4, 51.4 (2C), 45.5 (2C),44.8 (2C), 33.5, 32.7, 28.6, 21.1, 13.1.

Step 1k:N-Hydroxy-5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothien-[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)pentanamide(Compound 3)

To a stirred solution of hydroxylamine hydrochloride (4.67 g, 67 mmol)in methanol (24 mL) at 0° C. was added a solution of potassium hydroxide(5.61 g, 100 mmol) in methanol (14 mL). After addition, the mixture wasstirred for 30 minutes at 0° C. The resulting precipitate was filteredoff and the filtrate was prepared as free hydroxylamine solution.

The above freshly prepared hydroxylamine solution (4.00 mL) was placedin 10 mL flask. Compound 0115-3 (80 mg, 0.12 mmol) was added to thissolution and stirred at 0-10° C. for 15 minutes. The reaction processwas monitored by TLC. After the reaction was completed, the reaction wasfiltered. The collected solid was washed with water and methanol, driedto give compound 3 (45 mg, 58%) as a white solid: mp 139-143° C. LCMS:629 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (m, 2H), 1.83 (m, 2H), 1.98(t, J=7.4 Hz, 2H), 2.62 (s, 4H), 2.91 (s, 3H), 3.17 (s, 4H), 3.84 (s,4H), 3.86 (s, 2H), 4.01 (m, 4H), 4.47 (t, J=6.6 Hz, 2H), 7.52 (m, 2H),7.82 (d, J=8.4 Hz, 1H), 8.24 (d, J=6.8 Hz, 1H), 8.67 (s, 1H), 8.86 (s,1H), 10.36 (s, 1H).

Example 2 Preparation ofN-hydroxy-3-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)propanamide(Compound 4)

Step 2a: Ethyl6-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)hexanoate(Compound 0116-4) and ethyl3-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)propanoate(Compound 0115-4)

A mixture of compound 0114 (160 mg, 0.31 mmol), ethyl 6-bromohexanoate(83 mg, 0.37 mmol) and potassium carbonate (85 mg, 0.62 mmol) inacetonitrile (50 mL) was refluxed overnight. Solvent was removed and theresidue was partitioned between dichloromethane and water. The organiclayer was separated and washed with brine, dried over magnesium sulfate,filtered and evaporated in vacuo. The resulting residue was purified byprep-HPLC to give the title compound 0116-4 (40 mg, 20%) and 0115-4 (70mg, 34%).

Compound 0116-4: an oil; LCMS: 657 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ1.14 (t, J=7.2 Hz, 3H), 1.34 (m, 2H), 1.60 (m, 2H), 2.02 (m, 2H), 2.22(t, J=7.2 Hz, 2H), 2.62 (s, 4H), 2.73 (s, 3H), 3.23 (m, 4H), 3.82 (s,2H), 3.84 (m, 4H), 4.00 (m, 6H), 4.40 (t, J=7.2 Hz, 2H), 7.33 (m, 2H),7.74 (d, J=8.4 Hz, 1H), 8.19 (d, J=6.8 Hz, 1H), 8.82 (s, 1H). ¹³C NMR(100 MHz, CDCl₃): δ 172.4, 161.7, 159.6, 156.7, 148.6, 147.5, 130.1,124.6, 123.1, 122.1, 119.2, 118.8, 112.0, 65.8, 59.4, 56.4, 52.6, 51.2,45.3, 44.8, 33.3, 32.9, 29.3, 25.1, 23.4, 13.4.

Compound 0115-4: an oil; LCMS: 657 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ1.14 (t, J=7.2 Hz, 3H), 1.27 (m, 2H), 1.59 (m, 2H), 1.90 (m, 2H), 2.19(t, J=7.2 Hz, 2H), 2.61 (m, 4H), 2.72 (s, 3H), 3.22 (m, 4H), 3.83 (m,6H), 4.00 (m, 6H), 4.35 (t, J=7.2 Hz, 2H), 7.31 (s, 1H), 7.41 (m, 2H),8.16 (m, 1H), 8.81 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 172.6, 161.7,159.8, 157.1, 147.7, 139.2, 133.5, 131.2, 124.9, 123.2, 121.4, 120.7,112.1, 109.7, 65.8 (2C), 59.2, 56.3, 51.4, 47.7, 45.6, 44.8, 33.5, 33.0,28.6, 23.5, 19.8, 13.2.

Step 2b: N-hydroxy-3-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)propanamide(Compound 4)

The title compound 4 was prepared as a yellow solid (45 mg, 22%) from0115-4 (210 mg, 0.32 mmol) and freshly prepared hydroxylamine methanolsolution (5.0 mL) using a procedure similar to that described forcompound 3 (Example 1): mp 186-187° C. LCMS: 643 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.22 (m, 2H), 1.52 (m, 2H), 1.84-1.93 (m, 4H), 2.61 (m,4H), 2.91 (s, 3H), 3.17 (m, 4H), 3.82-3.85 (m, 4H), 3.95 (s, 2H),3.99-4.01 (m, 4H), 4.44 (t, J=6.8 Hz, 2H), 7.51 (m, 2H), 7.80 (d, J=8.8Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.63 (s, 1H), 8.85 (s, 1H), 10.30 (s,1H).

Example 3 Preparation ofN-hydroxy-7-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)heptanamide(Compound 5)

Step 3a: Ethyl7-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)heptanoate(Compound 0116-5) and ethyl7-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)heptanoate(Compound 0115-5)

The title compound 0115-5 (110 mg, 27%) and 0116-5 (60 mg, 16%) wereprepared from 0114 (280 mg, 0.55 mmol) , ethyl 7-bromoheptanoate (133mg, 0.65 mmol) and potassium carbonate (152 mg, 1.10 mmol) inacetonitrile (25 mL) using a procedure similar to that described forcompound 0115-3 and compound 0116-3 (Example 1):

Compound 0115-3 a white solid; LCMS: 670 [M+1]⁺; ¹H NMR (400 MHz,CDCl₃): δ 1.15 (t, J=7.2 Hz, 3H), 1.29 (m, 4H), 1.46 (m, 2H), 1.84 (m,2H), 2.23 (t, J=7.2 Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.16 (s, 4H),3.83 (m, 4H), 3.95 (s, 2H), 4.00 (m, 6H), 4.45 (t, J=6.6 Hz, 2H), 7.51(m, 2H), 7.79 (d, J=8.8 Hz, 1H), 8.23 (d, J=6.8 Hz 1H), 8.86 (s, 1H).

Compound 0116-3: a white solid; LCMS: 670 [M+1]⁺; ¹H NMR (400 MHz,CDCl₃): δ 1.14 (t, J=7.2 Hz, 3H), 1.31 (m, 4H), 1.53 (m, 2H), 1.97 (m,2H), 2.25 (t, J=7.6 Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.17 (s, 4H),3.83 (m, 4H), 3.95 (s, 2H), 4.00 (m, 6H), 4.50 (t, J=7.0 Hz, 2H), 7.37(t, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 8.17 (d, J=6.8Hz 1H), 9.02 (s, 1H).

Step 3b:N-hydroxy-7-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)heptanamide(Compound 5)

The title compound 5 was prepared as a white solid (70 mg, 71%) from0115-5 (100 mg, 0.15 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): mp 127-130° C. LCMS: 657 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.26 (s, 4H), 1.44 (m, 2H), 1.84 (m, 2H), 1.91 (t, J=7.2Hz, 2H), 2.61 (s, 4H), 2.91 (s, 3H), 3.16 (s, 4H), 3.83 (m, 4H), 3.95(s, 2H), 4.00 (m, 4H), 4.45 (t, J=6.8 Hz, 2H), 7.5 (m, 2H), 7.80 (d,J=8.4 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H), 8.65 (s, 1H), 8.86 (s, 1H), 10.32(s, 1H).

Example 4 Preparation ofN-hydroxy-5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)pentanamide(Compound 7)

The title compound 7 was prepared as a white solid (35 mg, 47%) from0116-3 (60 mg, 0.12 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): mp 146-169° C. LCMS: 629 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.57 (m, 2H), 2.00 (m, 2H), 2.07 (t, J=7.2 Hz, 2H), 2.67(s, 4H), 2.97 (s, 3H), 3.23 (s, 4H), 3.89 (s, 4H), 4.01 (s, 2H), 4.04(m, 4H), 4.57 (t, J=7.0 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.58 (s, 1H),7.81 (d, J=8.4 Hz, 1H), 8.28 (d, J=6.8 Hz, 1H), 9.08 (s, 1H).

Example 5 Preparation ofN-hydroxy-6-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)hexanamide(Compound 8)

The title compound 8 was prepared as a yellow solid (15 mg, 11%) from0116-4 (140 mg, 0.21 mmol) and freshly prepared hydroxylamine methanolsolution (5.0 mL) using a procedure similar to that described forcompound 3 (Example 1): mp 124-125° C. LCMS: 643 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.23 (m, 2H), 1.55 (m, 2H), 1.92-1.97 (m, 4H), 2.61 (m,4H), 2.91 (s, 3H), 3.17 (m, 4H), 3.82-3.85 (m, 4H), 3.95 (s, 2H),3.99-4.01 (m, 4H), 4.50 (t, J=6.8 Hz, 2H), 7.37 (m, 1H), 7.53 (s, 2H),7.74 (d, J=8.4 Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 8.64 (s, 1H), 9.02 (s,1H), 10.31 (s, 1H).

Example 6 Preparation ofN-hydroxy-7-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)heptanamide(Compound 9)

The title compound 9 was prepared as a white solid (45 mg, 76%) from0116-5 (60 mg, 0.09 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): mp 123-126° C. LCMS: 657 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.29 (s, 4H), 1.48 (m, 2H), 1.93 (m, 4H), 2.61 (s, 4H),2.91 (s, 3H), 3.16 (s, 4H), 3.83 (m, 4H), 3.95 (s, 2H), 3.98 (m, 4H),4.50 (t, J=7.0 Hz, 2H), 7.37 (t, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.75 (d,J=8.8 Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 8.65 (s, 1H), 9.03 (s, 1H), 10.32(s, 1H).

Example 7 Preparation of5-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxypentanamide(Compound 11)

Step 7a: Tert-butyl4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate(Compound 0201)

To a mixture of 0112 (4.0 g, 14.10 mmol) and tert-butylpiperazine-1-carboxylate (3.94 g, 21.15 mmol) in chloroform (50 mL) wasadded tetraisopyl titanate (4.81 g, 16.92 mmol). The mixture was stirredat room temperature overnight. The solvent was removed under reducedpressure. The residue was dissolved in ClCH₂CH₂Cl (60 mL) and NaBH₃CN(1.33 g, 21.15 mmol) was added to the mixture. The mixture was stirredat room temperature for 4 hours and was diluted with NaHCO₃ solution.The mixture was then extracted with ethyl acetate. The organic phase wasseparated, dried and concentrated to afford the product 0201 (5.2 g,81%): LCMS: 454 [M+1]⁺; ¹H NMR (400 Hz, CDCl₃) δ 1.46 (s, 9H), 2.49 (s,4H), 3.47 (t, J=4.4 Hz, 4H), 3.80 (s, 2H), 3.84 (t, J=5.2 Hz, 4H), 3.99(t, J=4.8 Hz, 4H), 7.17 (s, 1H).

Step 7b:4-(2-Chloro-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine(Compound 0202)

To a mixture of 0201 (5.2 g, 11.45 mmol) in dioxane was added 4 NHCl/dioxane (30 mL) under N₂. The reaction mixture was stirred at roomtemperature for 5 h. The mixture was poured into water (30 mL), adjustedpH 7 with saturated NaHCO₃ solution, extracted with ethyl acetate, driedand concentrated to afford the product 0202 (3.0 g, 74%): LCMS: 354[M+1]⁺; ¹H NMR (400 Hz, CDCl₃) δ 2.52 (s, 4H), 2.93 (t, J=4.8 Hz, 4H),3.78 (s, 2H), 3.84 (t, J=4.8 Hz, 4H), 3.99 (t, J=4.4 Hz, 4H), 7.16 (s,1H).

Step 7c: Ethyl5-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)pentanoate(Compound 0203-11)

To a mixture of 0202 (0.3 g, 0.85 mmol) in DMF (3 mL) was added Cs₂CO₃(0.61 g, 1.87 mmol) and ethyl 5-bromopentanoate (0.2 g, 0.93 mmol). Thereaction mixture was stirred at room temperature overnight and thenpoured into water (10 mL). The mixture was extracted with ethyl acetate.The organic phase was separated and washed with water (10 mL×5) andbrine, dried over Na₂SO₄, filtered and concentrated to afford theproduct 0203-11 (0.36 g, 80%) as a gray solid: LCMS: 482 [M+1]⁺; ¹H NMR(400 Hz, CDCl₃) δ 1.25 (t, J=7.2 Hz, 3H), 1.52-1.69 (m, 6H), 2.30-2.37(s, 2H), 2.55 (m, 6H), 3.79 (s, 2H), 3.84 (t, J=5.2 Hz, 4H), 3.98 (t,J=4.4 Hz, 4H), 4.13 (q, J=6.8 Hz, 2H), 7.16 (s, 1H).

Step 7d: Ethyl5-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)pentanoate(Compound 0204-11)

A mixture of 0203-11 (250 mg, 0.52 mmol), 0107-3 (140 mg, 0.57 mmol),NaHCO₃ (131 mg, 1.56 mmol) and Pd(dppf)₂Cl₂ (18 mg, 0.026 mmol) intoluene (4.8 mL), ethanol (2.5 mL) and water (1.3 mL) was flushed withN₂ and heated under microwave irradiation at 130° C. for 2 h. To themixture was added water (10 mL) and extracted with ethyl acetate. Theorganic phase was separated and washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby silica gel column (methanol in dichloromethane 5% v/v) to afford thetitle product 0204-11 as a white solid (62 mg, 21%): LCMS: 565 [M+2]⁺;¹H NMR (400 Hz, CDCl₃) δ 1.23 (m, 3H), 1.27 (m, 2H), 1.55 (m, 2H), 1.65(m, 2H), 2.32 (t, J=7.6 Hz, 2H), 2.40 (m, 2H), 2.54 (m, 2H), 2.64 (m,4H), 3.86 (s, 2H), 3.92 (t, J=4.8 Hz, 4H), 4.09 (t, J=5.2 Hz, 4H), 4.13(q, J=7.2 Hz, 2H), 7.38 (s, 1H), 7.50 (t, J=7.2 Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 8.28 (dd, J=7.2 Hz, 0.8 Hz, 1H), 9.01 (d, J=1.2 Hz, 1H).

Step 7e:5-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxypentanamide(Compound 11)

The title compound 11 was prepared as a white solid (21 mg, 17%) from0204-11 (129 mg, 0.23 mmol) and freshly prepared hydroxylamine methanolsolution (1.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): m.p. 125-127° C., LCMS: 552[M+2]⁺; ¹H NMR (400 Hz, DMSO-d₆) δ 1.23 (s, 2H), 1.39 (m, 2H), 1.48 (m,2H), 1.94 (t, J=7.6 Hz, 2H), 2.09 (s, 2H), 2.26 (t, J=6.8 Hz, 2H), 2.50(m, 4H), 2.64 (m, 4H), 3.86 (m, 6H), 4.00 (m, 4H), 7.47 (t, J=6.8 Hz,1H), 7.67 (d, J=8.4 Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 8.88 (s, 1H), 10.27(s, 1H), 13.20 (s, 1H).

Example 8 Preparation of 6-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxyhexanamide(Compound 12)

Step 8a: Ethyl6-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)hexanoate(Compound 0203-12)

The title compound 0203-12 was prepared as a gray solid (0.57 g, 82%)from 0202 (0.5 g, 1.41 mmol), Cs₂CO₃ (0.92 g, 2.82 mmol) and ethyl6-bromohexanoate (0.35 g, 1.55 mmol) using a procedure similar to thatdescribed for compound 0203-11 (Example 7): LCMS: 496 [M+1]⁺; ¹H NMR(400 Hz, CDCl₃) δ 1.25 (m, 4H), 1.34 (m, 2H), 1.64 (m, 2H), 2.30 (t,J=7.6 Hz, 2H), 2.38 (m, 2H), 2.60 (m, 8H), 3.80 (s, 2H), 3.84 (t, J=4.4Hz, 4H), 3.40 (t, J=4.8 Hz, 4H), 4.11 (q, J=7.2 Hz, 2H), 7.16 (s, 1H).

Step 8b: Ethyl6-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)hexanoate(Compound 0204-12)

The title compound 0204-12 was prepared as a white solid (56 mg, 16%)from 0203-12 (295 mg, 0.61 mmol), 0107-3 (164 mg, 0.67 mmol), NaHCO₃(150 mg, 1.79 mmol) and Pd(dppf)₂Cl₂ (23 mg, 0.031 mmol) in toluene (5.6mL), ethanol (3 mL) and water (1.5 mL) using a procedure similar to thatdescribed for compound 0204-11 (Example 7): LCMS: 579 [M+2]⁺; ¹H NMR(400 Hz, CDCl₃) δ 1.25 (t, J=7.6 Hz, 3H), 1.41 (m, 2H), 1.67 (m, 2H),1.81 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 3.02 (m, 8H), 3.61 (m, 2H), 3.96(m, 5H), 4.13 (q, J=14.4 Hz, 2H), 4.19 (m, 2H), 7.39 (t, J=7.2 Hz, 1H),7.55 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.97 (d, J=6.8 Hz, 1H), 8.50 (s,1H).

Step 8c:6-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxyhexanamide(Compound 12)

The title compound 12 was prepared as a white solid (15 mg, 13%) from0204-12 (120 mg, 0.21 mmol) and freshly prepared hydroxylamine methanolsolution (1.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): m.p. 123-124° C., LCMS: 565[M+1]⁺; ¹H NMR (400 Hz, DMSO-d₆) δ 1.23 (m, 2H), 1.26 (m, 2H), 1.36 (m,2H), 1.93 (t, J=7.2 Hz, 2H), 2.25 (t, J=6.8 Hz, 2H), 2.39 (m, 4H), 3.30(m, 4H), 3.85 (m, 6H), 4.00 (t, J=5.2 Hz, 4H), 7.47 (d, J=15.2 Hz, 2H),7.66 (d, J=8.4 Hz, 1H), 8.22 (d, J=6.8Hz, 1H), 8.65 (s, 1H), 8.88 (s,1H).

Example 9 Preparation of7-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxyheptanamide(Compound 13)

Step 9a: Ethyl7-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)heptanoate(Compound 0203-13)

The title compound 0203-13 was prepared as a gray solid (0.55 g, 76%)from 0202 (0.5 g, 1.41 mmol), Cs₂CO₃ (0.92 g, 2.82 mmol) and ethyl6-bromohexanoate (0.35 g, 1.55 mmol) using a procedure similar to thatdescribed for compound 0203-11 (Example 7): 512 [M+2]⁺; ¹H NMR (400 Hz,DMSO-d₆) δ 1.17 (t, J=6.8 Hz, 3H), 1.28 (m, 4H), 1.52 (m, 2H), 1.61 (m,2H), 2.28 (t, J=7.2 Hz, 2H), 2.49 (m, 4H), 3.05 (m, 6H), 3.75 (t, J=4.4Hz, 4H), 3.88 (t, J=4.8 Hz, 2H), 3.97 (m, 2H), 4.04 (q, J=14 Hz, 2H),7.34 (s, 1H).

Step 9b: Ethyl7-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)heptanoate(Compound 0204-13)

The title compound 0204-13 was prepared as a white solid (56 mg, 16%)from 0203-13 (300 mg, 0.60 mmol), 0107-3 (162 mg, 0.67 mmol), NaHCO₃(151 mg, 1.80 mmol) and Pd(dppf)₂Cl₂ (21 mg, 0.03 mmol) in toluene (5.5mL), EtOH (3 mL) and water (1.5 mL) using a procedure similar to thatdescribed for compound 0204-11 (Example 7): LCMS: 592 [M+1]⁺; ¹H NMR(400 Hz, CDCl₃) δ 1.25 (m, 3H), 1.33 (m, 4H), 1.51 (m, 2H), 1.63 (m,2H), 2.29 (t, J=7.6 Hz, 2H), 2.37 (m, 2H), 2.52 (m, 4H), 2.64 (m, 4H),3.86 (s, 2H), 3.92 (t, J=4.4 Hz, 4H), 4.09 (t, J=6.0 Hz, 4H), 4.12 (q,J=14.4 Hz, 2H), 7.38 (s, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz,1H), 8.28 (dd, J=7.6 Hz, 0.8 Hz, 1H), 9.02 (d, J=0.8 Hz, 1H).

Step 9c:7-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxyheptanamide(Compound 13)

The title compound 13 was prepared as a white solid (25 mg, 37%) from0204-13 (68 mg, 0.11 mmol) and freshly prepared hydroxylamine methanolsolution (0.5 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): m.p. 119-122° C., LCMS: 580[M+2]⁺; ¹H NMR (400 Hz, DMSO-d₆) δ 1.27 (m, 4H), 1.50 (m, 2H), 1.62 (m,2H), 1.94 (t, J=6.8 Hz, 2H), 2.47 (m, 4H), 3.06 (m, 6H), 3.85 (t, J=4.0Hz, 4H), 4.02 (m, 6H), 4.00 (t, J=5.2 Hz, 4H), 7.49 (t, J=8.4 Hz, 1H),7.56 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.87 (s,1H), 9.39 (s, 1H), 10.35 (s, 1H).

Example 10 Preparation of2-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 14)

Step 10a: (Z)-Ethyl-2-(ethoxymethyl)-3-methoxyacrylate (Compound 0302)

Sodium (13.8 g) was added to a mixture of benzene (200 mL) and ethanol(27 g) at room temperature. To the above mixture was added a mixture ofethyl formate (45.0 g, 0.61 mol) and ethyl 3-ethoxypropionate (44.0 g,0.30 mol) slowly at 0° C. The resulting reaction mixture was stirred for2 hours and then dimethyl sulfate (76.0 g, 0.61 mol) was added andstirred at 50° C. for 3 h. The mixture was filtered, and the filtratewas washed with water. The organic layer was separated and was addedtriethylammonium chloride (40.0 g, 0.29 mol) and sodium hydroxide (7.00g, 0.175 mol). The resulting mixture was stirred for 4 h. and thenfiltered. The filtrate was washed with water, dried over Na₂SO₄,filtered and evaporated to give a residue which was distilled undervacuum to provide compound 0302 (18.8 g, 33%) which was used directly tothe next step without further purification: ¹H NMR (400 MHz, CDCl₃): δ1.26 (m, 6H), 3.48 (m, 3H), 3.63 (m, 3H), 4.20 (m, 2H).

Step 10b: Ethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Compound 0303)

A mixture of compound 0302 (21.4 g, 0.11 mol), urea (5.70 g, 0.095 mol),and concentrated hydrochloric acid (36%˜38%, 5 mL) in ethanol (300 mL)was heated at reflux overnight. After evaporation, the residue wasrecrystallized from ethanol to give compound 0303 (7.80 g, 65%) as acolorless prisms: LCMS: 171 [M+1]⁺, ¹H NMR (400 MHz, CDCl₃): δ 1.27 (t,J=7.2 Hz, 3H), 4.19 (m, 4H), 5.28 (s, 1H), 7.21 (d, J=5.6 Hz, 1H), 7.40(s, 1H).

Step 10c: Ethyl 2-oxo-1,2-dihydropyrimidine-5-carboxylate (Compound0304)

A solution of compound 0303 (2.50 g, 14.7 mmol) and bromine (2.40 g, 15mmol) in acetic acid (55 mL) was heated at reflux for 1.5 h. Removal ofthe solvent afforded crude compound 0304 (3.60 g, 99%) which was useddirectly to the next step without further purification:. LCMS: 169[M+1]⁺, ¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=7.2 Hz, 3H), 4.28 (q,J=7.2 Hz, 2H), 8.85 (s, 2H), 12.19 (ds, 2H).

Step 10d: Ethyl 2-chloropyrimidine-5-carboxylate (Compound 0305)

A mixture of compound 0304 (3.60 g, 21 mmol), phosphorus oxychloride (25mL), and N,N-dimethylaniline (2.5 mL) was heated at reflux for 1.5 h.After removal of the solvent, ice water (10 mL) was added to theresidue. The mixture was added to 2 N NaOH (90 ml), and extracted withEtOAc. The organic layer was evaporated and purified by columnchromatography (ethyl acetate in petroleum ether, 5% v/v) to givecompound 0305 (1.20 g, 30%): LCMS: 187 [M+1]⁺, ¹H NMR (300 MHz, CDCl₃):δ 1.42 (t, J=7.5 Hz, 3H), 4.48 (q, J=7.5 Hz, 2H), 9.15 (s, 2H); ¹H NMR(400 MHz, DMSO-d₆): δ 1.33 (t, J=6.8 Hz, 3H); 4.37 (q, J=6.8 Hz, 2H),9.18 (s, 2H).

Step 10e: Ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate (Compound0306)

A mixture of compound 0305 (1.10 g, 5.9 mmol) and piperazine (1.02 g,11.8 mmol) in DMF (50 mL) was stirred at room temperature for 1.5 h. Themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and dried, concentrate to givecompound 0306 (1.20 g, 86%): LCMS: 237 [M+1]⁺, ¹H NMR (400 MHz,DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H), 2.73 (t, J=5.2 Hz, 4H), 3.77 (t,J=5.2 Hz, 4H), 4.25 (q, J=7.2 Hz, 2H), 8.76 (s, 2H).

Step 10f: Ethyl2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)pyrimidine-5-carboxylate(Compound 0307)

To a mixture of compound 0112 (500 mg, 1.77 mmol) and compound 0306 (376mg, 1.59 mmol) in chloroform (40 mL) was added tetraisopyl titanate (754mg, 2.66 mmol). The mixture was stirred at reflux overnight. Solvent wasevaporated and then 1,2-dichloroethane (50 mL) and sodiumcyanborohydride (168 mg, 2.66 mmol) were added. The resulting mixturewas stirred at room temperature for 12 h. The mixture was poured intosaturated NaHCO₃ and extract with ethyl acetate (2×50 mL). The organiclayer was separated and evaporated to afford a mixture which waspurified by silica gel column chromatography (ethyl acetate in petroleumether 10% v/v) to geve compound 0307 (270 mg, 34%) as a yellow solid:LCMS: 504 [M+1]⁻, ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J=6.8 Hz, 3H), 2.62(s, 4H), 3.85 (m, 6H), 4.00 (m, 8H), 4.33 (q, J=6.8 Hz, 2H), 7.26 (s,1H), 8.84 (s, 2H).

Step 10g: Ethyl2-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)pyrimidine-5-carboxylate(Compound 0308)

The title compound 0308 was prepared as a yellow solid (60 mg, 23%) from0307 (220 mg, 0.44 mmol), 0107-3 (161 mg, 0.66 mmol), NaHCO₃ (111 mg,1.32 mmol) and Pd(dppf)₂Cl₂ (19 mg, 0.022 mmol) in toluene (4.7 mL),ethanol (2.8 mL) and water (1.2 mL) using a procedure similar to thatdescribed for compound 0204-11 (Example 7): LCMS: 586 [M+1]⁺; ¹H NMR(400 MHz, CDCl₃): δ 1.35 (t, J=6.8 Hz, 3H), 2.66 (s, 4H), 3.93 (m, 6H),4.01 (m, 4H), 4.11 (m, 4H), 4.33 (q, J=6.8 Hz, 2H), 7.41 (s, 1H), 7.51(m, 1H), 7.69 (d, J=8.4 Hz, 1H), 8.28 (d, J=6.8 Hz, 1H), 8.84 (s, 2H),9.01 (s, 1H).

Step 10h:2-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 14)

The title compound 14 was prepared as a yellow solid (30 mg, 52%) from0308 (60 mg, 0.10 mmol) and freshly prepared hydroxylamine methanolsolution (3.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): mp 209-221° C. LCMS: 573 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 2.59 (s, 4H), 3.85 (m, 8H), 3.95 (s, 2H),4.01 (m, 4H), 7.47 (m, 1H), 7.52 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 8.23(d, J=6.8 Hz, 1H), 8.68 (s, 2H), 8.89 (s, 1H), 9.00 (s, 1H), 11.07 (s,1H), 13.19 (s, 1H).

Example 11 Preparation of2-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 15)

Step 11a: Ethyl2-(4-(aminomethyl)piperidin-1-yl)pyrimidine-5-carboxylate (Compound0401)

A mixture of 0405 (1.10 g, 5.9 mmol), piperidin-4-ylmethanamine (1.35 g,11.8 mmol) in 2-(dimethylamino)acetamide (50 mL) was stirred at roomtemperature for 1.5 h. After removal of the solvent, the residue waspurified by column chromatography on silica gel (CH3OH in CH2C12 6% v/v)to give desired product 0401 (1.27 g, 81%): LCMS: 265 [M+1]⁺, ¹H NMR(400 MHz, CDCl3): δ 1.16 (m, 2H), 1.22 (m, 5H), 1.36 (m, 1H), 1.64 (m,1H), 1.85 (d, J=12 Hz, 2H), 2.62 (d, J=6.42 Hz, 2H), 2.94 (ds, J=12.8Hz, J=2.4 Hz, 2H), 4.91 (d, J=11.2 Hz, 2H), 7.26 (s, 1H), 8.82 (s, 2H).

Step 11b: Ethyl2-(4-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate(Compound 0402-15)

To a mixture of compound 0112 (589 mg, 2.08 mmol) and compound 0401 (500mg, 1.89 mmol) in chloroform (50 mL) was added tetraisopyl titanate (644mg, 2.26 mmol). The mixture was stirred at reflux overnight. The solventwas removed and 1,2-dichloroethane (30 mL) and sodium cyanborohydride(179 mg, 2.84 mmol) were then added. The mixture was stirred at roomtemperature for 12 h. The mixture was poured into saturated NaHCO₃ andextract with ethyl acetate (2×50 mL). The organic layer was separatedevaporated. The residue was purified by column on silica gel (ethylacetate in petroleum ether 10% v/v) to give compound 0402 (630 mg, 57%).LCMS: 533 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.05-1.14 (m, 2H), 1.29(t, J=7.2 Hz, 3H), 1.78-1.85 (m, 3H), 2.46 (d, J=6.0 Hz, 2H), 2.68 (brs,1H), 2.98 (t, J=11 Hz, 2H), 3.75 (t, J=4.8 Hz, 4H), 3.88 (t, J=4.8 Hz,4H), 4.02 (s, 2H), 4.26 (t, J=7.2 Hz, 2H), 4.74 (d, J=13 Hz, 2H), 7.23(s, 1H), 8.74 (s, 2H).

Step 11c: Ethyl 2-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate(Compound 0403-15)

The title compound 0403 was prepared as a white solid (120 mg, 17%) from0402 (630 mg, 1.18 mmol), 0107-3 (580 mg, 2.37 mmol), NaHCO₃ (297 mg,3.54 mmol) and Pd(dppf)₂Cl₂ (25 mg, 0.036 mmol) in toluene (11 mL),ethanol (6.6 mL) and water (3.1 mL) using a procedure similar to thatdescribed for compound 0204-11 (Example 7): LCMS: 614 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆): δ 1.09-1.14 (m, 2H), 1.28 (t, J=7.2 Hz, 3H),1.82-1.87 (m, 3H), 3.00 (t, J=12 Hz, 2H), 3.83 (t, J=4.6 Hz, 4H), 4.01(t, J=4.6 Hz, 4H), 4.07 (s, 2H), 4.26 (t, J=7.2 Hz, 2H), 4.75 (d, J=13Hz, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.66 (d, J=8.0 Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 8.75 (s, 2H), 8.89 (s, 1H), 13.18 (s, 1H).

Step 11d:2-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 15)

The title compound 15 was prepared as a white solid (30 mg, 63%) from0403 (50 mg, 0.08 mmol) and freshly prepared hydroxylamine methanolsolution (3.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): mp 170-172° C. LCMS: 601 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 1.05-1.13 (m, 2H), 1.23 (m, 1H), 1.82-1.85(m, 3H), 2.95 (t, J=12 Hz, 2H), 3.84 (s, 4H), 4.01 (s, 4H), 4.07 (s,2H), 4.71 (d, J=13 Hz, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.66 (d, J=8.0 Hz,1H), 8.22 (d, J=7.2 Hz, 1H), 8.65 (s, 2H), 8.88 (s, 1H), 8.98 (s, 1H),11.03 (s, 1H), 13.18 (s, 1H).

Example 12 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 54)

Step 12a: (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol(Compound 0501)

To a mixture of compound 0112 (500 mg, 1.77 mmol) in methanol (10 mL)was added sodium borohydride (200 mg, 5.3 mmol). The mixture was stirredat room temperature for 1 hour. The reaction was quenched with water andextracted with ethyl acetate, dried over Na₂SO₄ and concentrated toobtain crude compound 0501 (500 mg, 99%) as a yellow solid: LCMS: 286[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆). δ 3.74 (t, J=4.4 Hz, 4H), 3.88 (t,J=4.4 Hz, 4H), 4.80 (d, J=5.6 Hz, 2H), 5.93 (t, J=5.6 Hz, 1H), 7.21 (s,1H).

Step 12b:4-(6-(Bromomethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine(Compound 0502)

To a solution of compound 0501 (1.6 g, 5.6 mmol) in dichloromethane (100mL) was added N-bromosuccinimide (1.2 g, 6.7 mmol) andtriphenylphosphine (1.75 g, 6.7 mmol). The mixture was stirred at 25° C.for 3 hours. Solvent was removed the residue was purified by columnchromatography (ethyl acetate in petroleum ether 20% v/v) to give titlecompound 0502 (1.16 mg, 60%) as a yellow solid: LCMS: 348 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆). δ 3.74 (t, J=4.8 Hz, 4H), 3.88 (t, J=4.4 Hz, 4H),4.79 (s, 2H), 7.21 (s, 1H).

Step 12c:(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine(Compound 0503-54)

A mixture of compound 0502 (190 mg) and methanamine alcohol solution (50mL) was stirred at reflux temperature for 1 hour. The solvent wasremoved at reduce pressure and the residue was purified by columnchromatography (methanol in dichloromethane, 12% v/v) to give titlecompound 0503-54 (190 mg, 54%) as a yellow solid: LCMS: 299 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 2.06 (s, 3H), 2.93 (s, 1H), 3.45 (t, J=4.4 Hz,4H), 3.57 (t, J=4.4 Hz, 4H), 3.73 (s, 2H), 7.02 (s, 1H).

Step 12d: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0504-54)

A mixture of compound 0503-54 (215 mg, 0.72 mmol), compound 0305 (336mg, 1.8 mmol) and N,N-diisopropylethylamine(20 mL) in acetonitrile (30mL) was stirred at room temperature overnight. The solvent was removedat reduce pressure and the resulting precipitation was washed with ethylacetate and dried to provide the title compound 0504-54 (210 mg, 65%) asa yellow solid: LCMS: 531 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.4 (t,J=6.8 Hz, 3H), 3.35 (s, 3H), 3.81 (t, J=4 Hz, 4H), 3.93 (t, J=4 Hz, 4H),4.38 (q, J=7.2 Hz, 2H), 5.31 (s, 2H), 7.05 (s, 1H), 8.97 (s, 2H).

Step 12e: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0505)

A mixture of compound 0504 (210 mg, 0.47 mmol), 0107-3 (171 mg, 0.7mmol), sodium hydrogen carbonate (118 mg, 1.4 mmol) andbis(triphenylphosphine)palladium(α) chloride (16 mg, 0.02 mmol) intoluene (5 mL), ethanol (3 mL) and water (1.3 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was added water and extracted with ethyl acetate. Theethyl acetate layer was collected and washed with brine, dried overmagnesium sulfate, filtered and evaporated to give a residue which waswashed with dichloromethane to obtain the title compound 0505-54 (130mg, 52%) as a white solid: LCMS: 449 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆):δ 1.37 (t, J=6.8 Hz, 3H), 3.36 (s, 3H), 3.86 (t, J=4.8 Hz, 4H), 4.02 (t,J=4.8 Hz, 4H), 4.35 (q, J=6.8 Hz, 2H), 5.33 (s, 2H), 7.53 (m, 1H), 7.66(s, 1H), 7.73 (d, J=8 Hz, 1H), 8.28 (d, J=7.2 Hz, 1H), 8.95 (dd, J₁=8Hz, J₂=7.6 Hz, 1H), 13.28 (s, 1H).

Step 12f:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 54)

The title compound 54 was prepared as a white solid (17 mg, 15%) from0505-54 (120 mg, 0.22 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): m.p. 197-200° C. LCMS: 518 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆): δ 3.26 (s, 3H), 3.86 (t, J=4.0 Hz, 4H), 3.96(t, J=4.0 Hz, 4H), 5.23 (s, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.58 (s, 1H),7.67 (d, J=8 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.76 (s, 2H), 8.87 (s,1H), 9.09 (s, 1H), 11.16 (s, 1H), 13.22 (s, 1H).

Example 13 Preparation of2-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide(Compound 53)

Step 13a: (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine(Compound 0503-53)

To a solution of compound 0502 (1.5 g, 4.3 mmol) in methanol (20 mL) wasadded NH₃.H₂O (20mL). The mixture was stirred overnight at 65° C. Thesolvent was removed at reduce pressure and the resulting residue waspurified by column chromatography (ethyl acetate in petroleum ether, 50%v/v) to give title compound 0503-53 (270 mg, 22%) as a yellow solid:LCMS: 285 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 3.75 (t, J=4.8 Hz, 4H),3.89 (t, J=4.4 Hz, 4H), 4.06 (s, 2H), 7.22 (s,1H).

Step 13b: Ethyl2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)pyrimidine-5-carboxylate(Compound 0504-53)

A mixture of compound 0503-53 (270 mg, 0.95 mmol), compound 0305 (353mg, 1.9 mmol) and N,N-Diisopropylethylamine(2 mL) in acetonitrile (10mL) was stirred at room temperature overnight. The solvent was removedat reduce pressure and the precipitation was washed withdichloromethane, dried to provide the title compound 0504-53 (160 mg,39%) as a white solid: LCMS: 435 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.29 (t, J=7.2 Hz, 3H), 3.72 (t, J=5.2 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H),4.27 (dd, J₁=14.0 Hz, J₂=6.8 Hz, 2H), 4.88 (d, J=6 Hz, 2H), 7.30 (s,1H), 8.79 (s, 2H), 8.85 (t, J=6 Hz, 1H).

Step 13c: Ethyl2-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)pyrimidine-5-carboxylate(Compound 0505-53)

A mixture of compound 0504-53 (160 mg, 0.37 mmol), 0107-3 (135 mg, 0.55mmol), sodium hydrogen carbonate (93 mg, 1.11 mmol) andbis(triphenylphosphine)palladium(α) chloride (13 mg, 0.02 mmol) intoluene (5 mL), ethanol (3 mL) and water (1.3 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was added water and extracted with ethyl acetate. Theorganic layer was collected and washed with brine, dried over magnesiumsulfate, filtered and evaporated to give a residue which was washed withdichloromethane to give title compound 0505-53 (80 mg, 42%) as a whitesolid: LCMS: 517 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t, J=6.8 Hz,3H), 3.81 (t, J=4.8 Hz, 4H), 3.97 (t, J=4.0 Hz, 4H), 4.27 (dd, J₁=14.0Hz, J₂=6.8 Hz, 2H), 4.93 (d, J=6.0 Hz, 2H), 7.45-7.50 (m,2H), 7.66 (d,J=8.0 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.81 (d, J=6.4 Hz, 2H), 8.88 (s,2H), 13.2 (s, 1H).

Step 13d:2-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide(Compound 53)

The title compound 53 was prepared as a light yellow solid (19 mg, 24%)from 0505-53 (80 mg, 0.15 mmol) and freshly prepared hydroxylaminemethanol solution (5.0 mL, 1.77 mol/L) using a procedure similar to thatdescribed for compound 3 (Example 1): m.p. 234-237° C. LCMS: 504 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆): δ 2.09 (s, 2H), 3.81 (t, J=4.8 Hz, 4H), 3.97(t, J=4.4 Hz, 4H), 4.90 (d, J=6.0 Hz, 2H), 7.47 (t, J=9.2 Hz, 2H), 7.66(d, J=8.4 Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.68(s, 2H), 8.88 (s, 1H), 9.04 (s, 1H), 11.09 (s, 1H), 13.21 (s, 1H).

Example 14 Preparation of2-(4-((((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 16)

Step 14a: Ethyl2-(4-((((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate(Compound 0402-16)

A compound of 0402-15 (510 mg, 0.96 mmol) and paraformaldehyde (58 mg,1.92 mmol) was solved in methanol (20 mL), then NaBH₃CN (121 mg, 1.92mmol) was added, the mixture was stirred at room temperature overnight.Methanol was removed and the residue was added ethyl acetate and water.The organic layer was washed by water and brine water, dried withanhydrous Na₂SO₄. Filtered, concentrated and the residue was purified bycolumn (ethyl acetate in petroleum ether 40% v/v) to get compound0402-16 (265 mg, 51%) as a yellow solid. LCMS: 546 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 1.04 (m, 2H), 1.28 (t, J=7.2, 3H), 1.84-1.88 (m, 3H),2.24 (s, 3H), 2.28 (d, J=6.8 Hz, 2H), 3.01 (t, J=11.6 Hz, 2H), 3.75 (m,4H), 3.83 (m, 2H), 3.88 (m, 4H), 4.25 (q, J=7.2 Hz, 2H), 4.74 (d, J=13.2Hz, 2H), 7.27 (s, 1H), 8.75 (s, 2H).

Step 14b: Ethyl2-(4-((((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate(Compound 0403-16)

A mixture of compound 0402-16 (246 mg, 0.45 mmol), 0107-3 (221 mg, 0.90mmol), sodium hydrogen carbonate (12.6 mg, 1.5 mmol) andbis(triphenylphosphine)palladium(II)chloride (19 mg, 0.023 mmol) intoluene (5 mL), ethanol (2.9 mL) and water (1.3 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 2 h. Thereaction mixture was partitioned between dichloromethane and water,organic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated in vacuo. The resulting residue was purifiedusing column chromatography eluting methanol in dichloromethane (2%,v/v), to give title compound 0403-16 (200 mg, 71%) as a yellow solid.LCMS: 628 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.18 (m, 2H), 1.35 (t,J=7.2 Hz, 3H), 1.94-1.97 (m, 3H), 2.34-2.36 (m, 5H), 2.97 (t, J=12.8 Hz,2H), 3.84 (m, 2H), 3.94 (m, 4H), 4.10 (m, 4H), 4.32 (q, J=7.2 Hz, 2H),4.90 (d, J=13.2 Hz, 2H), 7.36 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.57 (d,J=8.0 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.82 (s, 2H), 9.01 (s, 1H), 10.42(s, 1H).

Step 14c:2-(4-((((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(Compound 16)

To a stirred solution of hydroxylamine hydrochloride (4.67 g, 67 mmol)in methanol (24 mL) at 0° C. was added a solution of potassium hydroxide(5.61 g, 100 mmol) in methanol (14 mL). After addition, the mixture wasstirred for 30 minutes at 0° C., and was allowed to stand at lowtemperature. The resulting precipitate was isolated, and the solutionwas prepared to give free Hydroxylamine.

The above freshly prepared hydroxylamine solution (10.00 mL) was placedin 100 mL flask. Compound 111-47-2 (200 mg, 0.32 mmol) was added to thissolution and degassed at 0° C. for 15 minutes. The reaction process wasmonitored by TLC. The mixture was neutralized with dry ice, filtered andwashed with water, methanol and DCM to give the title compound 111-47(130 mg, 66%) as a yellow solid: mp 174-175° C. LCMS: 616 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 1.03 (m, 2H), 1.85-1.94 (m, 3H), 2.27-2.31 (m, 5H),2.97 (t, J=12.0 Hz, 2H), 3.84 (m, 6H), 4.00 (m, 4H), 4.71 (d, J=12.8 Hz,2H), 7.45-7.49 (m, 2H), 7.66 (d, J=8.4 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H),8.65 (s, 2H), 8.89 (s, 1H), 9.00 (s, 1H), 11.06 (s, 1H), 13.22 (s, 1H).

Example 15 Preparation of4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxybutanamide(Compound 41)

Step 15a: Ethyl4-(tert-butoxycarbonyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)butanoate(Compound 0404-41)

15a-1: Ethyl4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)butanoate

Ethyl 4-aminobutanoate hydrochloride (1.97 g, 11.77 mmol) was solved inchloroform (30 mL) and the pH of mixture was adjusted to 8-9 withtriethylamine, then compound 0112 (1.66 g, 5.88 mmol) and tetraisopyltitanate (2.01 g, 7.06 mmol) were added and the mixture was stirred atreflux overnight. Removed the solvent, then 1,2-dichloroethane (50 mL)and sodium cyanborohydride (1.48 g, 23.53 mmol) were added and thenstirred at room temperature for 12 h. The mixture was poured intosaturated NaHCO₃ solution and extract with ethyl acetate (3×50 mL) andpurified by column (ethyl acetate in petroleum ether 50% v/v) to get4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)butanoate(1.38 g, 59%) as a yellow solid. LCMS: 399 [M+1]⁺; ¹H NMR (400 MHz,CDCl₃) δ 1.15 (t, J=7.2 Hz, 3H), 1.68 (m, 2H), 2.35 (t, J=7.2 Hz, 2H),2.55 (t, J=7.2 Hz, 2H), 3.74 (t, J=4.8 Hz, 4H), 3.89 (t, J=4.8 Hz, 4H),4.00 (s, 2H), 4.03 (q, J=7.2 Hz, 2H), 7.25 (s, 1H).

15a-2: Ethyl4-(tert-butoxycarbonyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)butanoate(0404-41)

To a solution of4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)butanoate(400 mg, 1.0 mmol) in THF (10 mL) was added (Boc)₂O (218 mg, 1.0 mmol).Then the mixture was stirred at room temperature overnight. The reactionmixture was extracted with ethyl acetate and washed with water, brineand dried over sodium sulfate. The crude product was purified usingcolumn chromatography (ethyl acetate in petroleum ether 75% v/v), togive title compound 0404-41 (330 mg, 66%) as a colorless liquid. LCMS:499 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.16 (t, J=7.2 Hz, 3H), 1.42 (s,9H), 1.74 (m, 2H), 2.26 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.2 Hz, 2H), 3.74(t, J=4.4 Hz, 4H), 3.87 (t, J=4.4 Hz, 4H), 4.03 (q, J=7.2 Hz, 2H), 4.64(s, 2H), 7.30 (s, 1H).

Step 15b. Ethyl4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(tert-butoxycarbonyl)amino)butanoate(Compound 0405-41)

A mixture of compound 0404-41 (386 mg, 0.78 mmol), 0107-3 (378 mg, 1.55mmol), sodium hydrogen carbonate (196 mg, 2.33 mmol) andbis(triphenylphosphine)palladium(α)chloride (27 mg, 0.05 mmol) intoluene (8 mL), ethanol (5 mL) and water (2 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was partitioned between dichloromethane and water,organic layer was washed with brine, dried over sodium sulfate, filteredand evaporated in vacuum. The resulting residue was purified usingcolumn chromatography eluting methanol in dichloromethane (2-5%, v/v),to give title compound 0405-41 (396 mg, 79%) as a white solid. LCMS: 581[M+1]⁺; ¹H NMR (400 MHz, DMSO-d⁶): δ 1.16 (t, J=7.2 Hz, 3H), 1.44 (s,9H), 1.78 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 3.28 (t, J=6.8 Hz, 2H), 3.83(m, 4H), 4.03 (m, 6H), 4.70 (s, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.51 (s,1H), 7.67 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.88 (s, 1H), 13.22(s, 1H).

Step 15c:4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxybutanamide(Compound 41)

To a stirred solution of hydroxylamine hydrochloride (4.67 g, 67 mmol)in methanol (24 mL) at 0° C. was added a solution of potassium hydroxide(5.64 g, 100 mmol) in methanol (14 mL). After addition, the mixture wasstirred for 30 minutes at 0° C., and was allowed to stand at lowtemperature. The resulting precipitate was isolated, and the solutionwas prepared to give free Hydroxylamine.

The freshly prepared hydroxylamine solution (6.00 mL) was placed in 50mL flask. Compound 0405-41 (300 mg, 0.51 mmol) was added to thissolution and degassed at room temperature for 30 minutes. The reactionprocess was monitored by TLC. The mixture was neutralized with dry ice,filtered, and the precipitation was washed with methanol and water togivetert-butyl(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl(4-(hydroxyamino)-4-oxobutyl)carbamate(267 mg, 91%) as a white solid. LCMS: 568 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆):δ1.45 (s, 9H), 1.74 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 3.23 (m,2H), 3.83 (m, 4H), 4.00 (m, 4H), 7.47 (t, J=8.0 Hz, 1H), 7.50 (s, 1H),7.67 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.70 (s, 1H), 8.88 (s,1H), 10.39 (s, 1H), 13.22 (s, 1H).

The above prepared compound was then added to a freshly preparedisopropanol hydrogen chloride solution (7.00 mL). The reaction mixturewas stirred at room temperature for 2 h. The mixture was evaporated anddissolved in water. Then the mixture was neutralized with ammonia at 0°C., filtered and the precipitation was washed with methanol and water togive the crude product which was purified with pre-HPLC. Compound 41 wasgot (50 mg, 24%) as an orange solid: m.p. 149-152° C. LCMS: 468 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆):δ1.55 (m, 2H), 1.87 (t, J=7.2 Hz, 2H), 2.45(t, J=7.2 Hz, 2H), 3.68 (m, 4H), 3.86 (m, 6H), 3.96 (s, 2H), 7.32 (m,2H), 7.51 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 8.56(s, 1H), 8.73 (s, 1H), 13.06 (s, 1H).

Example 16 Preparation of5-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypentanamide(Compound 42)

Step 16a: Methyl5-(tert-butoxycarbonyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pentanoate(Compound 0404-42)

The title compound 0404-42 (0.75 g, 33.3%) was prepared as a white solidwithout further purification from 0112 (1.2 g, 4.24 mmol),5-aminopentanoate hydrochloride (1.416 g, 8.48 mmol) using a proceduresimilar to that described for compound 0404-41 (Example 15): LCMS: 399[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.39-1.47 (m, 2H), 1.52-1.60 (m,2H), 2.30 (t, J=7.2 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.74(t, J=4.8 Hz, 4H), 3.88 (t, J=4.8 Hz, 4H), 3.99 (s, 2H), 7.23 (s, 1H).Compound 0404-42: LCMS: 499 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ1.23 (s,9H),1.47-1.49 (m, 4H), 2.30 (t, J=6.8 Hz, 2H), 3.20 (s, 2H), 3.56 (s,3H), 3.74 (t, J=4.8 Hz, 4H), 3.88 (t, J=4.8 Hz, 4H), 4.64 (s, 2H), 7.31(s, 1H).

Step 16b: Methyl5-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(tert-butoxycarbonyl)amino)pentanoate(Compound 0405-42)

The title compound 0405-42 (260 mg, 55.8%) was prepared as a yellowsolid from 0404-42 (400 mg, 0.803 mmol), 0107-3 (216 mg, 0.884 mmol),sodium hydrogen carbonate (202.4 mg, 2.41 mmol) andbis(triphenylphosphine)palladium(α)chloride (30 mg, 0.0402 mmol) intoluene (8 mL), ethanol (5 mL) and water (2 mL) using a proceduresimilar to that described for compound 0404-42 (Example 15): LCMS: 581[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.44 (s, 9H), 1.50-1.52 (m, 4H),3.25 (s, 2H), 3.56 (s, 3H), 3.83 (d, J=5.2 Hz, 4H), 4.00-4.10 (m, 6H),4.69 (s, 2H), 7.47-7.51 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 8.23 (d, J=6.8Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).

Step 16c:5-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypentanamide(Compound 42)

The title compound 42 was prepared as a white solid (23 mg, 13.9%) from0405-42 (260 mg, 0.45 mmol) and freshly prepared hydroxylamine methanolsolution (8.0 mL) followed by deprotection using a procedure similar tothat described for compound 41 (Example 15): m.p 145-147° C. LCMS: 482[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.54-1.63 (m, 4H), 1.99 (t, J=7.2Hz, 2H), 3.02 (s, 2H), 3.87 (m, 4H), 4.05 (m, 4H), 4.58 (t, J=4.4 Hz,2H), 7.49 (t, J=8.4 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.78 (s, 1H), 8.24(d, J=10.4 Hz, 1H), 8.87 (s, 1H), 9.11 (s, 2H),10.42 (s, 1H), 13.28 (s,1H).

Example 17 Preparation of6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxyhexanamide(Compound 43)

Step 17a: Ethyl6-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)hexanoate(Compound 0404-43)

The title compound 0404-43 (343 mg, 38%) was prepared as a yellow solidfrom 0112 (0.6 g, 2.12 mmol) and ethyl 6-aminohexanoate hydrochloride(0.83 g, 4.24 mmol) using a procedure similar to that described forcompound 0404-41 (Example 15): LCMS: 427 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃)δ1.17 (t, J=6.4 Hz, 3H), 1.24-1.33 (m, 2H), 1.40-1.45 (m, 2H), 1.48-1.55(m, 2H), 2.09 (s, 1H), 2.27 (t, J=7.2 Hz, 2H), 2.53 (t, J=6.8 Hz 2H),3.74 (t, J=5.2 Hz, 4H), 3.88 (t, J=4.8 Hz, 4H), 3.99 (s, 2H), 4.03 (q,J=6.4 Hz, 2H), 7.23 (s, 1H).

Step 17b: Ethyl6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)hexanoate(Compound 0405-43)

A mixture of compound 0404-43 (343 mg, 0.80 mmol), 0107-3 (294 mg, 1.2mmol), sodium hydrogen carbonate (294 mg, 2.4 mmol) andbis(triphenylphosphine)palladium(α)chloride (29 mg, 0.05 mmol) intoluene (8 mL), ethanol (5 mL) and water (2 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was partitioned between dichloromethane and water,organic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated in vacuum. The resulting residue was purifiedusing column chromatography eluting methanol in dichloromethane (2-5%,v/v), to give title compound 0405-43 (120 mg, 29%) as a yellow solid.LCMS: 509 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.17 (t, J=7.2 Hz, 3H),1.28-1.35 (m, 2H), 1.42-1.57 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), 2.57 (t,J=6.8 Hz, 2H), 3.83 (t, J=4.0 Hz, 4H), 3.97-4.06 (m, 6H), 7.45 (s, 1H),7.47 (d, J=7.6 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H),8.88 (s, 1H), 13.21 (s, 1H).

Step 17c:6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxyhexanamide(43)

The title compound 43 was prepared (17 mg, 15%) as a yellow solid from0405-43 (120 mg, 0.24 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 128-130° C. LCMS: 496 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆):δ 1.23-1.32 (m, 2H), 1.42-1.53 (m, 4H), 1.95 (t, J=6.8 Hz,2H), 2.57 (t, J=7.2 Hz, 2H), 3.84 (t, J=4.0 Hz, 4H), 4.01 (t, J=4.0 Hz,4H), 4.06 (s, 2H), 7.45 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.66 (d, J=8Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.66 (s, 1H), 8.88 (s, 1H), 10.34 (s,1H), 13.21 (s, 1H).

Example 18 Preparation of7-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxyheptanamide(Compound 44)

Step 18a: Ethyl7-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)heptanoate(Compound 0404-44)

The title compound 0404-44 (700 mg, 45%) was prepared as a yellow solidfrom 0112 (1 g, 3.5 mmol) and 7-aminoheptanoate hydrochloride (1.5 g,7.0 mmol) using a procedure similar to that described for compound0404-41 (Example 15): LCMS: 442 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ1.16(t, J=7.2 Hz, 3H), 1.21-1.27 (m, 4H), 1.45 (m, 2H), 1.50 (m, 2H),2.21-2.28 (m, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.66 (s, 1H), 3.74 (t, J=5.2Hz, 4H), 3.88 (t, J=4.8 Hz, 4H), 4.00-4.06 (m, 4H), 7.23 (s, 1H).

Step 18b: Ethyl7-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)heptanoate(Compound 0405-44)

The title compound 0405-44 (260 mg, 63%) was prepared as a yellow solidfrom 0404-44 (350 mg, 0.79 mmol) and 0107-3 (290 mg, 1.19 mmol) using aprocedure similar to that described for compound 0405-43 (Example 17):LCMS: 523 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.16 (t, J=6 Hz, 3H),1.26-1.31 (m, 4H), 1.44 (m, 2H), 1.52 (m, 2H), 2.21-2.28 (m, 2H), 2.56(t, J=7.2 Hz, 2H), 3.83 (t, J=4.8 Hz, 4H), 4.01 (t, J=4.8 Hz, 4H), 4.04(s, 2H), 7.46 (m, 2H), 7.66 (d, J=8.4Hz, 1H), 8.22 (d, J=7.2 Hz, 1H),8.88 (s, 1H), 13.20 (s, 1H).

Step 18c:7-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxyheptanamide(Compound 44)

The title compound 44 was prepared (37 mg, 24%) as a yellow solid from0405-44 (160 mg, 0.31 mmol) and freshly prepared hydroxylamine methanolsolution (3.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 188-190° C. LCMS: 510 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆):δ 1.19-1.33 (m, 4H), 1.41-1.52 (m, 4H), 1.93 (t, J=7.2 Hz,2H), 2.56 (t, J=6.8 Hz, 2H), 3.83 (t, J=4.4 Hz, 4H), 4.01 (t, J=4.4 Hz,4H), 4.05 (s, 2H), 7.44 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.66 (d, J=8Hz, 1H), 8.22 (d, J=6.8 Hz, 2H), 8.68 (s, 1H), 8.88 (s, 1H), 10.34 (s,1H), 13.21 (s, 1H).

Example 19 Preparation of4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxybutanamide(Compound 101)

Step 19a: Ethyl4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)butanoate(Compound 0404-101)

To a solution of ethyl4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)butanoate(100 mg, 0.25 mmol) in methanol (5 mL) was added poly-formaldehyde (15mg, 0.50 mmol). After stirred for 30 min at room temperature, NaBH₃CN(32 mg, 0.50 mmol) was added slowly, and the mixture was stirred foranother 30 min. The reaction was terminated by adding water (5 mL) at 0°C. and stirred. The resulting precipitate was filtered and washed withwater to give 0404-101 (85 mg, 83%) as a yellow solid. LCMS: 413 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 1.14 (t, J=7.2 Hz, 3H), 1.72 (m, 2H), 2.22(s, 3H), 2.32 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 3.75 (t, J=4.4Hz, 4H), 3.82 (s, 2H), 3.88 (t, J=4.4 Hz, 4H), 4.02 (q, J=7.2 Hz, 2H),7.27 (s, 1H).

Step 19b: Ethyl4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)butanoate(Compound 111-48-3)

The title compound 0405-101 (200 mg, 56%) was prepared as a yellow solidfrom 0404-101 (300 mg, 0.73 mmol) and 0107-3 (356 mg, 1.46 mmol) using aprocedure similar to that described for compound 0405-43 (Example 17):LCMS: 495 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ1.15 (t, J=7.2 Hz, 3H), 1.75(m, 2H), 2.25 (s, 3H), 2.35 (t, J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H),3.83 (m, 6H), 4.02 (m, 6H), 7.47 (m, 2H), 7.67 (d, J=8.0 Hz, 1H), 8.22(d, J=8.0 Hz, 1H), 8.89 (s, 1H), 13.21 (s, 1H).

Step 19c:4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxybutanamide(Compound 101)

The title compound 101 was prepared (160 mg, 88%) as a yellow solid from0405-101 (187 mg, 0.38 mmol) and freshly prepared hydroxylamine methanolsolution (6.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 115-118° C. LCMS: 482 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆):δ 1.72 (m, 2H), 2.02 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 2.42(t, J=6.0 Hz, 2H), 3.85 (m, 6H), 4.01 (m, 4H), 7.47 (m, 2H), 7.67 (d,J=7.6 Hz, 1H), 8.22 (d, J=6.8 Hz, 1H), 8.89 (s, 1H), 13.26 (s, 1H).

Example 20 Preparation of5-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypentanamide(Compound 102)

Step 20a: Methyl5-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pentanoate(Compound 0404-102)

The title compound 0404-102 (0.62 g, 86%) was prepared as a white solidfrom Methyl5-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)pentanoate(700 mg, 1.76 mmol), paraformaldehyde (106 mg, 3.52 mmol) in methanol(30 mL) and NaBH3CN (221 mg, 3.52 mmol) using a procedure similar tothat described for compound 0404-101 (Example 19): LCMS: 413 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 1.45-1.59 (m, 4H), 2.21 (s, 3H), 2.32 (t, J=6.8Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.75 (t, J=5.2 Hz, 4H),3.81 (s, 2H), 3.88 (t, J=4.8 Hz, 4H), 7.26 (s, 1H).

Step 20b: Methyl5-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pentanoate(Compound 0405-102)

The title compound 0405-102 (305 mg, 61.7%) was prepared as a yellowsolid from 0404-102 (350 mg, 0.85 mmol) and 0107-3 (311 mg, 1.27 mmol)using a procedure similar to that described for compound 0405-43(Example 17): LCMS: 495 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.48-1.57(m, 4H), 2.24 (s, 3H), 2.34 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.8 Hz, 2H),3.58 (s, 3H),3.84 (d, J=8.4 Hz, 6H), 3.97-4.04 (m, 4H), 7.49 (m, 2H),7.67 (d, J=8.4 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.88 (s, 1H), 13.20 (s,1H).

Step 20c:5-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypentanamide(Compound 102)

The title compound 102 was prepared (60 mg, 25%) as a yellow solid from0405-102 (240 mg, 0.48 mmol) and freshly prepared hydroxylamine methanolsolution (8.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 120-122° C. LCMS: 496 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.48-1.54 (m, 4H), 1.98 (t, J=6.8 Hz, 2H), 2.24 (s, 3H),2.44 (t, J=7.2 Hz, 2H), 3.85 (d, J=6.8 Hz, 4H), 4.01 (s, 4H), 7.46 (s,2H), 7.66 (d, J=7.2 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.88 (s, 1H), 10.31(s, 1H), 13.18 (s, 1H).

Example 21 Preparation of6-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxyhexanamide(Compound 103)

Step 21a: Ethyl6-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)hexanoate(Compound 0404-103)

The title compound 0404-103 (0.62 g, 86%) was prepared as a white solidfrom 0404-43 (0.67 g, 1.57 mmol), paraformaldehyde (94 mg, 3.14 mmol)and NaBH3CN (197 mg, 3.14 mmol) using a procedure similar to thatdescribed for compound 0404-101 (Example 19): LCMS: 441 [M+1]⁺; 1H NMR(400 MHz, DMSO-d₆): δ 1.16 (t, J=7.2 Hz, 3H), 1.24-1.32 (m, 2H),1.43-1.55 (m, 4H), 2.21 (s, 3H), 2.27 (t, J=7.2 Hz, 2H), 2.39 (t, J=7.6Hz, 2H), 3.75 (t, J=4.8 Hz, 4H), 3.81 (s, 2H), 3.88 (t, J=4.4 Hz, 4H),4.03 (q, J=7.2 Hz, 2H), 7.26 (s, 1H).

Step 21b: Ethyl6-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)hexanoate(Compound 0405-103)

The title compound 0405-103 (190 mg, 54%) was prepared as a yellow solidfrom 0404-103 (300 mg, 0.68 mmol) and 0107-3 (199 mg, 0.82 mmol) using aprocedure similar to that described for compound 0405-43 (Example 17):LCMS: 523 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (t, J=7.2 Hz, 3H),1.28-1.35 (m, 2H), 1.47-1.57 (m, 4H), 2.27 (m, 5H), 2.41 (t, J=6.4 Hz,2H), 3.84 (m, 6H), 4.04 (m, 6H), 7.47 (m, 2H), 7.67 (d, J=8 Hz, 1H),8.23 (d, J=6.8 Hz, 1H), 8.89 (s, 1H), 13.21 (s, 1H).

Step 21c:6-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxyhexanamide(Compound 103)

The title compound 103 was prepared (75 mg, 41%) as a white solid from0405-103 (190 mg, 0.22 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 115-118° C. LCMS: 510 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆):δ 1.23-1.27 (m, 2H), 1.45-1.55 (m, 4H), 1.95 (t, J=7.2 Hz,2H), 2.24 (s, 3H), 2.42 (t, J=7.2 Hz, 2H), 3.84 (m, 6H), 4.00 (m, 4H),7.47 (m, 2H), 7.66 (d, J=8.4 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.68 (s,1H), 8.89 (s, 1H), 10.35 (s, 1H), 13.21 (s, 1H).

Example 22 Preparation of7-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxyheptanamide(Compound 104)

Step 22a: Ethyl7-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)heptanoate(Compound 0404-104)

The title compound 0404-104 (670 mg, 95%) was prepared as a yellow solidfrom 0404-44 (0.67 g, 1.52 mmol), paraformaldehyde (91 mg, 3.04 mmol)and NaBH3CN (191 mg, 3.04 mmol) using a procedure similar to thatdescribed for compound 0404-101 (Example 19): LCMS: 455 [M+1]+; 1H NMR(400 MHz, DMSO-d6): δ1.16 (t, J=7.2 Hz, 3H), 1.23-1.32 (m, 4H),1.42-1.54 (m, 4H), 2.21 (s, 3H), 2.25 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.2Hz, 2H), 3.74 (t, J=4 Hz, 4H), 3.80 (s, 2H), 3.88 (t, J=4.8 Hz, 4H),4.03 (q, J=7.2 Hz, 2H), 7.25 (s, 1H).

Step 22b: Ethyl7-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)heptanoate(Compound 0405-104)

The title compound 0405-104 (260 mg, 67%) was prepared as a yellow solidfrom 0404-104 (330 mg, 0.73 mmol) and 0107-3 (176 mg, 0.73 mmol) using aprocedure similar to that described for compound 0405-43 (Example 17):LCMS: 537 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.14 (t, J=7.2 Hz, 3H),1.28-1.41 (m, 4H), 1.49-1.55 (m, 4H), 2.25 (m, 5H), 2.41 (t, J=6.8 Hz,2H), 3.83 (m, 6H), 4.01 (m, 6H), 7.46 (m, 2H), 7.65 (d, J=7.6 Hz, 1H),8.21 (d, J=6.8 Hz, 1H), 8.87 (s, 1H), 13.17 (s, 1H).

Step 22c:7-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxyheptanamide(Compound 104)

The title compound 104 was prepared (65 mg, 55%) as a white solid from0405-104 (120 mg, 0.22 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 131-133° C. LCMS: 524 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆):δ 1.21-1.27 (m, 4H), 1.34-1.43 (m, 4H), 1.94 (t, J=7.6 Hz,2H), 2.24 (s, 3H), 2.43 (t, J=7.6 Hz, 2H), 3.84 (m, 6H), 4.00 (m, 4H),7.47 (m, 2H), 7.67 (d, J=8 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.68 (s,1H), 8.89 (s, 1H), 10.34 (s, 1H), 13.21 (s, 1H).

Example 23 Preparation of2-(((2-(6-fluoro-1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 69)

Step 23a: 3-Bromo-5-fluoro-2-methylbenzenamine (Compound 0104-69)

To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) intrifluoroacetic acid (40 mL) was added con. sulfuric acid (12.5 mL)followed by NBS (17.2 g, 96.6 mmol) and the reaction mixture was stirredat room temperature for 16 h. Then the reaction mixture was poured intoice and water and stirred for 15 min. Extracted with ethyl acetate andthe organic layer was washed with brine, dried, concentrated to getcompound 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (15.0 g, 100%) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 2.41 (s, 3H), 7.96 (dd, J=8.0,2.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz, 1H). A mixture of above preparedcompound (15.0 g, 64.4 mmol), Fe (18.0 g, 0.32 mol), con. HCl (2 mL) inMeOH (150 mL) and water (30 mL) was stirred at reflux for 4 h. Then themixture was adjusted to pH 12 with aqueous NaOH solution and filtered.The solvent was removed and diluted with water. Extracted with ethylacetate, dried, concentrated. The residue was purified by columnchromatograph (ethyl acetate in petroleum ether, 7%) to get compound0104-69 (5.8 g, 44%) as yellow oil. LCMS: 204 [M+1]⁺, ¹H NMR (400 MHz,DMSO-d₆) δ 2.12 (s, 3H), 5.57 (s, 2H), 6.45 (dd, J=11.2, 2.4 Hz, 1H),6.60 (dd, J=8.0, 2.4 Hz, 1H).

Step 23b: 4-Bromo-6-fluoro-1H-indazole (Compound 0106-69)

The title compound 0106-69 (3.7 g, 61%) was prepared as a yellow solidfrom 0104-69 (5.8 g, 28.4 mmol), potassium acetate (2.93 g, 29.8 mmol),Ac2O (5.8 g, 56.8 mmol) and iso-amyl nitrite (7.32 g, 62.5 mmol)followed by hydrolysis by aqueous hydrochloric acid (6N, 35 mL) using aprocedure similar to that described for compound 0106-3 (Example 1):LCMS: 215 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.44 (m, 2H), 8.07(s, 1H), 13.54 (s, 1H).

Step 23c:6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(Compound 107-69)

The title compound 0107-69 (700 mg, 57%) was prepared as a yellow solidfrom 0106-69 (1.0 g, 4.65 mmol), bis(pinacolato)diboron (1.77 g, 6.98mmol), PdCl2(dppf)2 (380 mg, 0.47 mmol) and dried potassium acetate(1.37 g, 14.0 mmol) in dioxane (40 mL) using a procedure similar to thatdescribed for compound 0107-3 (Example 1): LCMS: 263 [M+1]⁺.

Step 23d: Ethyl2-(((2-(6-fluoro-1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0505-69)

A mixture of compound 0504-54 (200 mg, 0.45 mmol), 0107-69 (135 mg, 0.5mmol), sodium hydrogen carbonate (115 mg, 1.3 mmol) andbis(triphenylphosphine)palladium(II)chloride (15 mg, 0.02 mmol) intoluene (8 mL), ethanol (5mL) and water (2 mL) was flushed with nitrogenand heated under microwave irradiation at 120° C. for 5 h. The reactionmixture was partitioned between ethyl acetate and water, organic layerwas washed with brine, dried over sodium sulfate, filtered, concentratedand washed with ethyl acetate to obtain the title compound 0505-69 (100mg, 41%) as a yellow solid. LCMS: 549 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆):δ 1.30 (t, J=7.2 Hz, 3H), 3.29 (s, 3H), 3.79 (t, J=4.4 Hz, 4H), 3.96 (t,J=4.4 Hz, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.27 (s, 2H), 7.46 (d, J=7.2 Hz,1H), 7.62 (s, 1H), 7.98 (dd, J=10.4 Hz, 2.4 Hz, 1H), 8.94 (m, 3H), 13.27(s, 1H).

Step 23e:2-(((2-(6-Fluoro-1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 69)

The title compound 69 was prepared (24 mg, 25%) as a yellow solid from0505-69 (100 mg, 0.18 mmol) and freshly prepared hydroxylamine methanolsolution (10.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 215-217° C. LCMS: 536 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.26 (s, 3H), 3.79 (m, 4H), 3.96 (m, 4H), 5.24 (s, 2H),7.46 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 7.98 (dd, J=10.8, 2.0 Hz, 1H),8.76 (s, 2H), 8.89 (s, 1H), 9.08 (s, 1H), 11.14 (s, 1H), 13.28 (s, 1H).

Example 24 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(neopentyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 83)

Step 24a:N-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,2-dimethylpropan-1-amine(Compound 0503-83)

The solution of compound 0503-53 (600 mg, 2.1 mmol), pivalaldehyde (912mg, 10.6 mmol) and Ti(OEt)₄ (958 mg, 4.2 mmol) in CHCl₃/MeOH (8 mL/4 mL)was stirred at 35° C. for 20 hr. Then NaBH₃CN (530 mg, 8.4 mmol) wasadded and stirred for 3 hr at 45° C. This mixture was diluted with H₂O,extracted with CH₂Cl₂, dried by Na₂SO₄, and concentrated to obtain0503-83 (631 mg, 85%) as a yellow solid. LCMS: 355 [M+1]⁺. ¹H-NMR (400MHz, DMSO-d₆) δ 0.95 (s, 9H), 2.29 (s, 2H), 3.74 (m, 4H), 3.88 (m, 4H),4.02 (s, 2H), 7.23 (s, 1H).

Step 24b: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(neopentyl)amino)pyrimidine-5-carboxylate(Compound 0504-83)

A mixture of compound 0503-83 (400 mg, 1.13 mmol), 0305 (846 mg, 4.52mmol) and DIPEA (1.5 g, 11.3 mmol) in MeCN (8 mL) was stirred at 70° C.for 24 hr, concentrated, purified by column chromatograph (ethyl acetatein petroleum ether, 10% v/v) to provide compound 0504-83 (530 mg, 93%)as a yellow solid. LCMS: 505 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 0.97(s, 9H), 1.29 (m, 3H), 3.67 (s, 2H), 3.72 (m, 4H), 3.87 (m, 4H), 4.27(m, 2H), 5.19 (s, 2H), 7.35 (s, 1H), 8.84 (s, 2H).

Step 24c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(neopentyl)amino)pyrimidine-5-carboxylate(Compound 0505-83)

A mixture of compound 0504-83 (300 mg, 0.6 mmol), 0107-3 (176 mg, 0.72mmol), NaHCO₃ (152 mg, 1.8 mmol) andbis(triphenylphosphine)palladium(II)chloride (22 mg, 0.03 mmol) intoluene (4 mL), ethanol (2 mL) and water (1 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 1 h. Thereaction mixture was partitioned between dichloromethane and water,organic layer was washed with brine, dried over Na₂SO₄, filtered andevaporated in vacuum. The resulting residue was purified using columnchromatography (methanol in dichloromethane, 2-5% v/v) to give titlecompound 0505-83 (300 mg, 85%) as a white solid. LCMS: 587 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 0.99 (s, 9H), 1.29 (t, J=7.2 Hz, 3H), 3.70 (s,2H), 3.79 (m, 4H), 3.95 (m, 4H), 4.27 (q, J=7.6 Hz, 2H), 5.24 (s, 2H),7.46 (t, J=7.6 Hz, 1H), 7.55 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 8.21 (d,J=7.2 Hz, 1H), 8.85 (s, 2H), 8.89 (s, 1H), 13.21 (s, 1H).

Step 24d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(neopentyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 83)

The title compound 83 was prepared (191 mg, 65%) as a yellow solid from0505-83 (300 mg, 0.51 mmol) and freshly prepared hydroxylamine methanolsolution (20.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 240-242° C. LCMS: 574 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 0.99 (s, 9H), 3.67 (s, 2H), 3.80 (m, 4H), 3.95 (m, 4H),5.22 (s, 2H), 7.46 (t, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.67 (d, J=8.0 Hz,1H), 8.21 (d, J=7.2 Hz, 1H), 8.73 (s, 2H), 8.89 (s, 1H), 9.07 (s, 1H),11.12 (s, 1H), 13.20 (s, 1H).

Example 25 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(propyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 84)

Step 25a:N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)propan-1-amine(Compound 0503-84)

Compound 0502 (500 mg, 1.43 mmol) was dissolved in methanol (30 mL) andthen propan-1-amine (5 mL) was added. The mixture was stirred at 65° C.and the reaction process was monitored by TLC. Then the solvent wasremoved at reduce pressure and the precipitation was partitioned betweendichloromethane and water, organic layer was washed with brine and driedover sodium sulfate anhydrous, filtered, evaporated in vacuum and thenpurified by column chromatography (methanol in dichloromethane, 1.7%v/v) to give title compound 0503-84 (412 mg, 88%) as a light yellowsolid. LCMS: 327 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (t, J=7.4 Hz,3H), 1.39-1.48 (m, 2H), 2.49 (t, J=2.0 Hz, 2H), 2.82 (s, 1H), 3.73 (t,J=4.8 Hz, 4H), 3.87 (t, J=4.8 Hz, 4H), 4.00 (s, 2H), 7.23 (s, 1H).

Step 25b: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(propyl)amino)pyrimidine-5-carboxylate(Compound 0504-84)

The title compound 0504-84 was prepared (477 mg, 79%) as a yellow solidfrom 0503-84 (412 mg, 1.26 mmol) and 0305 (353 mg, 1.89 mmol) inacetonitrile (30 mL), and N,N-Diisopropylethylamine (3 mL) using aprocedure similar to that described for compound 0504-83 (Example 24):LCMS: 477 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.86 (t, J=7.6 Hz, 3H),1.30 (t, J=7.2 Hz, 3H), 1.57-1.66 (m, 2H), 3.65 (t, J=7.6 Hz, 2H), 3.71(t, J=4.8 Hz, 4H), 3.83 (t, J=4.6 Hz, 4H),4.28 (q, J=7.2 Hz, 2H), 5.17(s, 2H), 7.42 (s, 1H), 8.86 (s, 2H).

Step 25c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(propyl)amino)pyrimidine-5-carboxylate(Compound 0505-84)

The title compound 0505-84 was prepared (240 mg, 82%) as a white solidfrom 0504-84 (250 mg, 0.52 mmol), 0107-3 (154 mg, 0.63 mmol), sodiumhydrogen carbonate (132 mg, 1.57 mmol) andbis(triphenylphosphine)palladium(II)chloride (18.5 mg, 0.026 mmol) intoluene (8 mL), ethanol (5 mL) and water (2 mL) using a proceduresimilar to that described for compound 0505-83 (Example 24): LCMS: 559[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 0.88 (t, J=7.2 Hz, 3H), 1.30 (t,J=7.0 Hz, 3H), 1.61-1.71 (m, 2H), 3.70 (t, J=7.4 Hz, 2H), 3.80 (t, J=4.6Hz, 4H), 3.96 (t, J=4.6 Hz, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.23 (s, 2H),7.47 (t, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 8.22 (d,J=6.8 Hz, 1H), 8.88 (s, 3H), 13.20 (s, 1H).

Step 25d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(propyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 84)

The title compound 84 was prepared (189 mg, 81%) as a white solid from0505-84 (240 mg, 0.43 mmol) and freshly prepared hydroxylamine methanolsolution (16.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 224-226° C. LCMS: 546 [M+1]⁻; ¹H NMR (400MHz, DMSO-d₆) δ 0.88 (t, J=7.4 Hz, 3H), 1.60-1.69 (m, 2H), 3.67 (t,J=7.6 Hz, 2H), 3.80 (t, J=4.4 Hz, 4H), 3.96 (t, J=4.8 Hz, 4H), 5.20 (s,2H), 7.47 (t, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 8.22(d, J=6.8 Hz, 1H), 8.75 (s, 2H), 8.88 (s, 1H), 9.07 (s, 1H), 11.12 (s,1H), 13.20 (s, 1H).

Example 26 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(butyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 85)

Step 26a:N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)butan-1-amine(Compound 0503-85)

The title compound 0503-85 was prepared (430 mg, 88%) as a light yellowsolid from 0502 (500mg, 1.43 mmol) and butan-1-amine (5mL) in methanol(30 mL) using a procedure similar to that described for compound 0503-84(Example 25): LCMS: 341 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (t,J=7.4 Hz, 3H), 1.33-1.42 (m, 2H), 1.45-1.52 (m, 2H), 2.61 (t, J=7.0 Hz,2H), 2.90 (s, 1H), 3.81-3.82 (m, 4H), 3.94-3.95 (d, 4H), 4.07 (s, 2H),7.30 (s, 1H).

Step 26b: Ethyl2-(butyl((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0504-84)

The title compound 0504-85 was prepared (519 mg, 84%) as a light yellowsolid from 0503-85 (430 mg, 1.26 mmol) and (353 mg, 1.89 mmol) inacetonitrile (30 mL) and N,N-Diisopropylethylamine(3 mL) using aprocedure similar to that described for compound 0504-83 (Example 24):LCMS: 491 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 0.88 (t, J=7.4 Hz, 3H),1.26-1.34 (m, 5H), 1.55-1.62 (m, 2H), 3.67-3.72 (m, 6H), 3.83 (t, J=4.8Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 5.17 (s, 2H), 7.41 (s, 1H), 8.86 (s,2H).

Step 26c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(butyl)amino)pyrimidine-5-carboxylate(Compound 0505-85)

The title compound 0505-85 was prepared (255 mg, 87%) as a light yellowsolid from 0504-85 (250 mg, 0.51 mmol), 0107-3 (149 mg, 0.61 mmol),sodium hydrogen carbonate (128 mg, 1.53 mmol) andbis(triphenylphosphine)palladium(α)chloride (17.8 mg, 0.025 mmol) intoluene (8 mL), ethanol (5 mL) and water (2 mL) using a proceduresimilar to that described for compound 0505-83 (Example 24): LCMS: 573[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.04 (t, J=7.4 Hz, 3H), 1.43-1.48(m, 5H), 1.73-1.81 (m, 2H), 3.88 (t, J=7.6 Hz, 2H), 3.94 (t, J=4.6 Hz,4H), 4.10 (t, J=4.6 Hz, 4H), 4.43 (q, J=7.1 Hz, 2H), 5.37 (s, 2H), 7.61(t, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 8.36 (d, J=6.8Hz, 1H), 9.02 (s, 3H), 13.34 (s, 1H).

Step 26d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(butyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 85)

The title compound 85 was prepared (131 mg, 53%) as an off-white solidfrom 0505-85 (255 mg, 0.45 mmol) and freshly prepared hydroxylaminemethanol solution (16.0 mL) using a procedure similar to that describedfor compound 3 (Example 1): m.p. 234-236° C. LCMS: 560 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆): δ 0.96 (t, J=7.4 Hz, 4H), 4.02 (t, J=4.4 Hz, 4H),5.26 (s, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.73 (d, J=8.4 Hz,1H), 8.28 (d, J=7.2 Hz, 1H), 8.81 (s, 2H), 8.94 (s, 1H), 9.14 (s, 1H),11.18 (s, 1H), 13.27 (s, 1H).

Example 27 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 86)

Step 27a:2-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)ethanol(Compound 0503-86)

The title compound 0503-86 was prepared (230 mg, 41%) as a light yellowsolid from 0502 (600 mg, 1.72 mmol) and 2-aminoethanol (6 mL) inmethanol (60 mL) using a procedure similar to that described forcompound 0503-84 (Example 25): LCMS: 329 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 2.62 (t, J=5.8 Hz, 2H), 2.74 (s, 1H), 3.47 (dd, J₁=11.2 Hz,J₂=6.0 Hz, 2H), 3.73 (t, J=4.8 Hz, 4H), 3.88 (t, J=5.0 Hz, 4H), 4.04(s,2H), 4.53 (t, J=5.2 Hz, 1H), 7.24 (s,1H).

Step 27b: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)amino)pyrimidine-5-carboxylate(Compound 0504-86)

The title compound 0504-86 was prepared (170 mg, 51%) as a white solidfrom 0503-86 (230 mg, 0.7 mmol) and 0305 (157 mg, 0.84 mmol).inacetonitrile (20 mL) and N,N-Diisopropylethylamine (4 mL) using aprocedure similar to that described for compound 0504-83 (Example 24):LCMS: 479 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H),3.62 (dd, J₁=11.2 Hz, J₂=6.0 Hz, 2H), 3.70 (t, J=4.6 Hz, 4H), 3.76 (t,J=6.0 Hz, 2H), 3.82 (t, J=4.6 Hz, 4H), 4.27 (dd, J₁=13.6 Hz, J₂=6.8 Hz,2H), 4.86 (t, J=5.2 Hz, 1H), 5.23 (s, 2H), 7.39 (s, 1H), 8.85 (s, 2H).

Step 27c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)amino)pyrimidine-5-carboxylate(0505-86)

The title compound 0505-86 was prepared (120 mg, 60%) as a white solidfrom 0504-86 (170 mg, 0.35 mmol), 0107-3 (104 mg, 0.43 mmol), sodiumhydrogen carbonate (89 mg, 1.06 mmol) andbis(triphenylphosphine)palladium(α)chloride (13 mg, 0.02 mmol) intoluene (4 mL), ethanol (2.5 mL) and water (1 mL) using a proceduresimilar to that described for compound 0505-83 (Example 24): LCMS: 561[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t, J=6.8 Hz, 3H), 3.66 (dd,J₁=10.8 Hz, J₂=5.6 Hz, 2H), 3.78-3.83 (m, 6H), 3.95 (t, J=4.6 Hz, 4H),4.28 (dd, J₁=14.4 Hz, J₂=7.2 Hz, 2H), 4.88 (t, J=5.4 Hz, 1H), 5.29 (s,2H), 7.46 (t, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 8.21(d, J=7.2 Hz, 1H), 8.87 (s, 3H), 13.2 (s, 1H).

Step 27d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-hydroxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide(86)

The title compound 86 was prepared (42 mg, 36%) as an off-white solidfrom 0505-86 (120 mg, 0.21 mmol) and freshly prepared hydroxylaminemethanol solution (8.0 mL) using a procedure similar to that describedfor compound 3 (Example 1): m.p. 190-194° C. LCMS: 548 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆): δ 3.64 (dd, J₁=10.8 Hz, J₂=5.6 Hz, 2H), 3.79 (dd,J₁=8.4 Hz, J₂=4.4 Hz, 6H), 3.95 (t, J=4.4 Hz, 4H), 4.85 (t, J=5.2 Hz,1H), 5.25 (s, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 8.74 (s, 2H), 8.87 (s, 1H), 9.07 (s,1H), 11.13 (s, 1H), 13.20 (s, 1H).

Example 282-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-methoxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 90)

Step 28a:N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methoxyethanamine(Compound 0503-90)

The title compound 0503-90 was prepared (410 mg, 80%) as oil from 0502(520 mg, 1.5 mmol) and 2-methoxyethanamine (1.1 g. 10.0 mmol) inmethanol (20 mL) using a procedure similar to that described forcompound 0503-84 (Example 25): LCMS: 343 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃)δ 2.858 (t, J=7.2 Hz, 3H), 3.37 (s, 3H), 3.53 (t, J=5.2 Hz, 2H), 3.53(t, J=5.2 Hz, 2H), 3.83 (t, J=5.2 Hz, 4H), 3.99 (t, J=4.8 Hz, 4H), 4.12(s, 2H), 7.16 (s, 1H).

Step 28b: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-methoxyethyl)amino)pyrimidine-5-carboxylate(Compound 0504-90)

The title compound 0504-90 was prepared (400 mg, 81%) as a yellow solidfrom 0503-90 (342 mg, 1.0 mmol) and 0305 (205 mg, 1.1 mmol) inacetonitrile (20 mL) and N,N-Diisopropylethylamine (400mg, 3.3 mmol)using a procedure similar to that described for compound 0504-83(Example 24): LCMS: 493 [M+1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 1.29 (t,J=6.8 Hz, 3H), 3.22 (s, 3H), 3.56 (t, J=5.2 Hz, 2H), 3.70 (brs, 4H),3.82 (brs, 4H), 3.88 (t, J=5.2 Hz, 2H), 4.27 (q, J=6.8 Hz, 2H), 5.19 (s,2H), 7.39 (s, 1H), 8.86 (s, 1H).

Step 28c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-methoxyethyl)amino)pyrimidine-5-carboxylate(Compound 0505-90)

The title compound 0505-90 was prepared (260 mg, 90%) as a white solidfrom 0504-90 (246 mg, 0.5 mmol), 0107-3 (146 mg, 0.6 mmol), sodiumhydrogen carbonate (126 mg, 1.5 mmol) andbis(triphenylphosphine)palladium(α)chloride (18 mg, 0.025 mmol) intoluene (8.0 mL), ethanol (5 mL) and water (3 mL) using a proceduresimilar to that described for compound 0505-83 (Example 24): LCMS: 575[M+1]⁺ ¹H NMR (400 MHz, DMSO₆) δ 1.38 (t, J=7.2 Hz, 3H), 3.44 (s, 3H),3.69 (t, J=5.6 Hz, 2H), 3.87 (m, 4H), 4.02 (m, 6H), 4.27 (q, J=7.2 Hz,2H), 5.34 (s, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.67 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 8.30 (d, J=6.8 Hz, 1H), 8.97 (s, 2H), 13.29 (s, 1H).

Step 28d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(2-methoxyethyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 90)

The title compound 90 was prepared (180 mg, 71%) as a white solid from0505-90 (260 mg, 0.45 mmol) and freshly prepared hydroxylamine methanolsolution (15.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 219-222° C. LCMS: 482 [M+1]⁻. ¹H-NMR (400MHz. DMSO-d₆) δ 3.26 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 3.79 (m, 4H), 3.90(t, J=5.6 Hz, 2H), 3.95 (m, 4H), 5.22 (s, 2H), 7.46 (t, J=7.2 Hz, 1H),7.56 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.74 (s,2H), 8.87 (s, 1H), 9.07 (brs, 1H), 11.12 (s, 1H), 13.19 (s, 1H).

Example 29 Preparation of2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(isobutyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 93)

Step 29a:N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methylpropan-1-amine(Compound 0503-93)

The title compound 0503-93 was prepared (0.6 g, 88%) as a yellow solidfrom 0502 (694 g, 2.0 mmol), 2-methylpropan-1-amine (1.5 g, 20 mmol) andDIPEA (2.6 g, 20 mmol) in MeOH (5 mL) using a procedure similar to thatdescribed for compound 0503-84 (Example 25): LCMS: 341 [M+1]⁺. ¹H-NMR(400 MHz, DMSO-d₆) δ 0.87 (d, J=6.8 Hz, 6H), 1.69 (m, 1H), 2.35 (d,J=6.8 Hz, 2H), 2.60 (s, 1H), 3.74 (m, 4H), 3.88 (m, 4H), 4.00 (s, 2H),7.23 (s, 1H).

Step 29b: Ethyl2-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(isobutyl)amino)pyrimidine-5-carboxylate(Compound 0504-93)

The title compound 0504-93 was prepared (500 mg, 57%) as a yellow solidfrom 0503-93 (613 mg, 1.8 mmol) and 0305 (675 mg, 3.6 mmol) inacetonitrile (8 mL) and N,N-Diisopropylethylamine (1.2 g, 9 mmol) usinga procedure similar to that described for compound 0504-83 (Example 24):LCMS: 491 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 0.87 (d, J=6.8 Hz, 6H),1.29 (t, J=7.2 Hz, 3H), 2.17 (m, 1H), 3.58 (d, J=7.6 Hz, 2H), 3.71 (m,4H), 3.83 (m, 4H), 4.28 (q, J=7.2 Hz, 2H), 5.17 (s, 2H), 7.41 (s, 1H),8.85 (s, 2H).

Step 29c: Ethyl2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(isobutyl)amino)pyrimidine-5-carboxylate(Compound 0505-93)

The title compound 0505-93 was prepared (257 mg, 91%) as a white solidfrom 0504-93 (245 mg, 0.5 mmol), 0107-3 (147 mg, 0.6 mmol), sodiumhydrogen carbonate (126 mg, 1.5 mmol) andbis(triphenylphosphine)palladium(α)chloride (18 mg, 0.025 mmol) intoluene (4.0 mL), ethanol (2 mL) and water (1 mL) using a proceduresimilar to that described for compound 0505-83 (Example 24): LCMS: 573[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 0.89 (d, J=6.8 Hz, 6H), 1.29 (m,3H), 2.20 (m, 1H), 3.60 (d, J=7.6 Hz, 2H), 3.79 (m, 4H), 3.95 (m, 4H),4.27 (m, 2H), 5.21 (s, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.68(d, J=8.4 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.86 (s, 2H), 8.90 (s, 1H),13.22 (s, 1H).

Step 29d:2-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(isobutyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 93)

The title compound 93 was prepared (90 mg, 26%) as a white solid from0505-93 (357 mg, 0.6 mmol) and freshly prepared hydroxylamine methanolsolution (20.0 mL) using a procedure similar to that described forcompound 3 (Example 1): m.p. 196-198° C. LCMS: 560 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 0.89 (d, J=6.4 Hz, 6H), 2.20 (m, 1H), 3.59 (d, J=7.6 Hz,2H), 3.80 (m, 4H), 3.96 (m, 4H), 5.20 (s, 2H), 7.47 (t, J=8.0 Hz, 1H),7.59 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.75 (s,2H), 8.90 (s, 1H), 9.12 (s, 1H), 11.14 (s, 1H), 13.23 (s, 1H).

Example 30 Preparation of6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxynicotinamide(Compound 76)

Step 30a: Isopropyl6-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)nicotinate(Compound 0309-76)

To a suspension of 0112 (3.4 g, 12 mmol) and ethyl 6-aminonicotinate(912 mg, 6 mmol) in toluene (50 mL) was added tetraisopropyl titanate (2g, 7.2 mmol) and the mixture was stirred at 120° C. overnight.NaBH(OAc)₃ (1.9 g, 9 mmol) was added to the reaction mixture, then themixture was cooled to room temperature and stirred for additional 4hours, extracted with dichloromethane (10 mL×2). The combined organiclayer was washed with saturated NaHCO₃ (aq., 20 mL), brine (20 mL×2),dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v)to obtain 0309-76 (1.5 g, 28%) as a white solid. LCMS: 448 [M+1]⁺;¹H-NMR (400 MHz. DMSO-d₆) δ 1.29 (d, J=6 Hz, 6H) 3.73 (m, 4H), 3.85 (m,4H), 4.89 (d, J=5.6 Hz, 2H), 5.09 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.81(s, 1H), 7.31 (s, 1H), 7.86 (d, J=2 Hz, 1H), 8.58 (s, 1H).

Step 30b: Methyl6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)nicotinate(Compound 0310-76)

The isopropyl6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-nicotinatewas prepared (200 mg, 82%) as a yellow solid from 0309-76 (200 mg, 0.462mmol), 0107-3 (124 mg, 0.51 mmol), sodium hydrogen carbonate (120 mg,1.4 mmol) and bis(triphenylphosphine)palladium(II)chloride (16 mg,0.0231 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL) using aprocedure similar to that described for compound 0505-83 (Example 24):LCMS: 530 [M+1]⁺ ¹H-NMR (400 MHz. DMSO-d₆) δ 1.28 (d, J=6 Hz, 6H) 3.81(m, 4H), 3.98 (m, 4H), 4.94 (d, J=5.6 Hz, 2H), 5.08 (m, 1H), 6.67 (d,J=8.8 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.51 (s, 1H), 7.677 (d, J=8.4 Hz,1H), 7.90 (d, J=2.4 Hz, 1H), 8.21 (d, J=7.6 Hz, 2H), 8.60 (s, 1H), 8.87(s, 1H), 13.20 (s, 1H).

To a mixture of above compound (200 mg, 0.378 mmol) in MeOH (8 mL) wasadded dropwise conc. H₂SO₄ (2 ml). The mixture was refluxed overnight.Evaporated to give the crude methyl ester, 0310-76 (140 mg, 75%) whichwas used in next step directly without further purification. LCMS: 502[M+1]⁺ ¹H-NMR (400 MHz. DMSO-d₆) δ 3.77 (s, 3H), 3.81 (m, 4H), 3.98 (m,4H), 4.94 (d, J=5.6 Hz, 2H), 6.67 (d, J=8.8 Hz, 1H), 7.47 (t, J=8.4 Hz,1H), 7.51 (s, 1H), 7.677 (d, J=8.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.21(d, J=7.6 Hz, 2H), 8.62 (s, 1H), 8.87 (s, 1H), 13.21 (s, 1H).

Step 30c:6-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxynicotinamide(Compound 76)

The title compound 76 was prepared (23 mg, 16%) as a brown solid from0310-76-2 (140 mg, 0.28 mmol) and freshly prepared hydroxylaminemethanol solution (10.0 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p 218-220° C. LCMS: 503 [M+1]⁻. ¹H-NMR(400 MHz. DMSO-d₆): δ 3.81 (m, 4H), 3.98 (m, 4H), 4.90 (d, J=4.8 Hz,2H), 6.62 (d, J=6.8 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 7.50 (s, 1H), 7.62(d, J=8 Hz, 1H), 7.78 (d, J=4 Hz, 1H), 7.89 (t, J=4.8 Hz, 1H), 8.21 (d,J=6.4 Hz, 1H), 8.43 (s, 1H), 8.85 (s, 1H), 10.95 (s, 1H), 13.19 (s, 1H).

Example 31 Preparation of4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxybenzamide(Compound 78)

Step 31a: Ethyl4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)benzoate(Compound 0309-78)

The title compound, 0309-78 was prepared (580 mg, 95%) as an orangesolid from ethyl 4-aminobenzoate (256 mg, 1.55 mmol), 0112 (400 mg, 1.41mmol) and tetraisopyl titanate (480 mg, 1.69 mmol) using a proceduresimilar to that described for compound 0309-76 (Example 30). LCMS: 433[M+1]¹; ¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (t, J=7.2 Hz, 3H), 3.71 (t,J=4.8 Hz, 4H), 3.83 (t, J=4.6 Hz, 4H), 4.20 (q, J=5.3 Hz, 2H), 4.71 (d,J=6.0 Hz, 2H), 6.68 (d, J=9.2 Hz, 2H), 7.35 (t, J=6.4 Hz, 1H), 7.36 (s,1H), 7.69 (d, J=8.4 Hz, 2H).

Step 31b: Ethyl4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)benzoate(Compound 0310-78)

The title compound, 0310-78 was prepared (85 mg, 33%) as a white solidfrom 0309-78 (216 mg, 0.5 mmol), 0107-3 (256 mg, 0.53 mmol), sodiumhydrogen carbonate (126 mg, 1.5 mmol) andbis(triphenylphosphine)palladium(II) chloride (18 mg, 0025 mmol) intoluene (4.0 mL), ethanol (2.5 mL) and water (1.5 mL) using a proceduresimilar to that described for compound 0310-76 (Example 30). LCMS: 515[M+1]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 (t, J=7.2 Hz, 3H), 3.80 (t,J=4.6 Hz, 4H), 3.97 (t, J=4.6 Hz, 4H), 4.20 (q, J=5.3 Hz, 2H), 4.75 (d,J=6.0 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 7.39 (t, J=6.0 Hz, 1H), 7.47 (t,J=8.0 Hz, 1H), 7.56 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz,2H), 8.22 (d, J=7.2 Hz, 1H), 8.88 (s, 1H).

Step 31c:4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxybenzamide(Compound 78)

The title compound 78 was prepared (41 mg, 28%) as a yellow solid from0310-78 (150 mg, 0.29 mmol) and freshly prepared hydroxylamine methanolsolution (10.0 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 180-183° C. LCMS: 502 [M+1]⁻; ¹H NMR (400MHz, DMSO-d₆) δ 3.80 (br s, 4H), 3.96 (t, 4H), 4.72 (d, J=5.6 Hz, 2H),6.68 (d, J=8.8 Hz, 2H), 7.09 (t, J=6.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H),7.54 (d, J=8.4 Hz, 2H), 7.57 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 8.22 (d,J=7.2 Hz, 1H), 8.72 (s, 1H), 8.87 (s, 1H), 10.81 (s, 1H), 13.22 (s, 1H).

Example 32 Preparation of(E)-3-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)phenyl)-N-hydroxyacrylamide(Compound 80)

Step 32a: (E)-ethyl3-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)phenyl)acrylate(Compound 0309-80)

The title compound, 0309-80 was prepared (968 mg, 71%) as a light yellowsolid from (E)-ethyl 3-(4-aminophenyl)acrylate (623 mg, 3.26 mmol), 0112(840 mg, 2.96 mmol), and tetraisopyl titanate (1 g, 3.55 mmol) using aprocedure similar to that described for compound 0309-76 (Example 30).LCMS: 459 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H),3.71 (t, J=4.6 Hz, 4H), 3.83 (t, J=4.6 Hz, 4H), 4.13 (q, J=7.2 Hz, 2H),4.69 (d, J=6.0 Hz, 2H), 6.27 (d, J=16.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H),7.17 (t, J=6.0 Hz,1H), 7.36 (s, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.48 (d,J=16.0 Hz, 1H).

Step 32b: (E)-ethyl3-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)phenyl)acrylae(Compound 0310-80)

The title compound, 0310-80 was prepared (490 mg, 69%) as a light yellowsolid from 0309-80 (600 mg, 1.31 mmol), 0107-3 (383 mg, 1.57 mmol),sodium hydrogen carbonate (329 mg, 3.92 mmol) andbis(triphenylphosphine)palladium(II) chloride (46 mg, 0.065 mmol) intoluene (16.0 mL), ethanol (10 mL) and water (4 mL) using a proceduresimilar to that described for compound 0310-76 (Example 30). LCMS: 541[M+1]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H), 3.82 (t,J=4.0 Hz, 4H), 3.97 (t, J=4.4 Hz, 4H), 4.12 (q, J=7.2 Hz, 2H), 4.74 (d,J=5.2 Hz, 2H), 6.27 (d, J=15.6 Hz, 1H), 6.70 (d, J=8.8 Hz, 2H), 7.21 (t,J=5.8 Hz, 1H), 7.45-7.50 (m, 4H), 7.57 (s, 1H), 7.67 (d, J=8.0 Hz, 1H),8.22 (d, J=6.8 Hz, 1H), 8.87 (s, 1H), 13.21 (s, 1H).

Step 32c:(E)-3-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)phenyl)-N-hydroxyacrylamide(Compound 80)

The title compound 80 was prepared (71 mg, 15%) as a light yellow solidfrom 0310-80 (490 mg, 0.91 mmol) and freshly prepared hydroxylaminemethanol solution (20.0 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p.>300° C. LCMS: 528 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.87 (t, J=4.6 Hz, 4H), 4.03 (t, J=4.6 Hz, 4H), 4.78 (d,J=5.6 Hz, 2H), 6.21 (d, J=15.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 7.11 (t,J=5.8 Hz, 1H), 7.34-7.39 (m, 3H), 7.53 (t, J=7.8 Hz, 1H), 7.63 (s, 1H),7.73 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 8.93 (d, J=4.8 Hz, 2H),10.60 (s, 1H), 13.27 (s, 1H).

Example 33 Preparation of(E)-3-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)phenyl)-N-hydroxyacrylamide(Compound 81)

Step 33a: (E)-ethyl3-(4-(((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)phenyl)acrylate(Compound 0309-81)

The solution of compound 0309-80 (1.0 g, 2.2 mmol), CH₃I (6.2 g, 44mmol), and Cs₂CO₃ (1.44 g, 4.4 mmol) in dry CH₃CN/DMF solution (5 mL/5mL) was stirred at room temperature for 3 days. CH₃I and CH₃CN wasremoved in vacuo and the residue was diluted with H₂O, extracted withethyl acetate, dried over Na₂SO₄, and the crude product was purified bycolumn chromatography on silica gel (ethyl acetate in petroleum ether,20% v/v) to obtain 0309-81 (0.3 g, 30%) as a yellow solid. LCMS: 473[M+1]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 1.23 (t, J=7.2 Hz, 3H), 3.12 (s,3H), 3.70 (m, 4H), 3.82 (m, 4H), 4.14 (q, J=7.2 Hz, 2H), 4.97 (s, 2H),6.33 (d, J=16.4 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.31 (s, 1H), 7.53 (m,3H).

Step 33b: (E)-ethyl3-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)phenyl)acrylate(Compound 0310-81)

The title compound, 0310-81 was prepared (200 mg, 71%) as a white solidfrom 0309-81 (240 mg, 0.5 mmol), 0107-3 (135 mg, 0.55 mmol), NaHCO₃ (126mg, 1.5 mmol), and bis(triphenylphosphine)palladium(II) chloride (18 mg,0.025 mmol) in toluene (4 mL), ethanol (2 mL) and water (1 mL) using aprocedure similar to that described for compound 0310-76 (Example 30).LCMS: 555 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.23 (m, 3H), 3.17 (s,3H), 3.80 (m, 4H), 3.95 (m, 4H), 4.15 (m, 2H), 5.01 (s, 2H), 6.33 (d,J=15.6 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.46 (m, 1H), 7.54 (m, 4H), 7.66(d, J=8.0 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.87 (s, 1H), 13.21 (s, 1H).

Step 33c:(E)-3-(4-(((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)phenyl)-N-hydroxyacrylamide(Compound 81)

The title compound 81 was prepared (24 mg, 10%) as a light yellow solidfrom 0310-81 (250 mg, 0.45 mmol) and freshly prepared hydroxylaminemethanol solution (20.0 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 188-190° C. LCMS: 542 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 3.14 (s, 3H), 3.80 (m, 4H), 3.95 (m, 4H), 4.98 (s,2H), 6.21 (d, J=15.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.32 (d, J=15.2Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.50 (s, 1H),7.66 (d, J=8.0 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.34 (s, 1H), 8.87 (s,1H), 10.58 (s, 1H), 13.23 (s, 1H).

Example 34 Preparation of(2-(((2-(3-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 107)

Step 34a: N-(3-bromophenyl)acetamide (Compound 0601-107)

To the solution of 3-bromoaniline (6.3 g, 63.7mmol) in CH₂Cl₂ (50 mL)was added acetyl chloride (3.75 g, 47.7 mmol) and TEA (7.4 g, 73.4 mmol)at 0° C., stirred for 2 hours. The mixture was washed with water, brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure togive the title compound 0601-107 (7.8 g, 99.3%) as a brown solid. LCMS:215 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (s, 3H), 7.22 (m, 2H), 7.46(d, J=7.6 Hz, 1H), 7.95 (s, 1H), 10.11 (s, 1H).

Step 34b:N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(Compound 0602-107)

To a solution of compound 0601-107 (2.5 g, 11.6 mmol) andbis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was addedpotassium acetate (3.4 g, 35 mmol) and PdCl₂(dppf)₂ (0.95 g, 1.1 mmol).The mixture was degassed with nitrogen and heated at 85° C. forovernight. The reaction mixture was concentrated under reduced pressureto afford the crude product, which purified by column chromatography(ethyl acetate in petroleum ether, 15% v/v) to give the compound0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d,J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s,1H).

Step 34c: Ethyl2-(((2-(3-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-107)

The title compound, 0603-107 was prepared (160 mg, 99%) as a gray solidfrom 0504-54 (130 mg, 0.30 mmol), 0602-107 (84 mg, 0.7 mmol), sodiumhydrogen carbonate (74 mg, 0.88 mmol) andbis(triphenylphosphine)palladium(II) chloride (12 mg, 0.014 mmol) intoluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a proceduresimilar to that described for compound 0310-76 (Example 30). LCMS: 548[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.31 (t, J=6.8 Hz, 3H), 2.07 (s,3H), 3.27 (s, 1H), 3.77 (t, J=5.2 Hz, 4H), 3.94 (t, J=5.2 Hz, 4H), 4.29(q, J=7.2 Hz, 2H), 5.24 (s, 2H), 7.39 (t, J=8.4 Hz, 1H), 7.49 (s, 1H),7.82 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.52 (s, 1H), 8.89 (s,2H), 10.08 (s, 1H).

Step 34d:2-(((2-(3-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 107)

The title compound 107 was prepared (64 mg, 50%) as a white solid from0603-107 (130 mg, 0.23 mmol) and freshly prepared hydroxylamine methanolsolution (4.0 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 183-185° C. LCMS: 535 [M+1]⁻; ¹H NMR (400MHz, DMSO-d₆):δ 2.07 (s, 3H), 3.24 (s, 3H), 3.77 (t, J=4.0 Hz, 4H), 3.94(t, J=4.0 Hz, 4H), 5.21 (s, 2H), 7.39 (t, J=8 Hz, 1H), 7.46 (s, 1H),7.82 (d, J=7.6 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 8.51 (s, 1H), 8.75 (s,2H), 9.07 (s, 1H), 10.08 (s, 1H), 11.13 (s, 1H).

Example 35 Preparation of2-(((2-(3-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 108)

Step 35a: Ethyl6-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)hexanoate(Compound 0602-108)

The title compound, 0602-108 was prepared (600 mg, 80%) as oil from3-bromo-N,N-dimethylaniline (600 mg, 3.0 mmol), bis(pinacolato)diboron(1.14 g, 4.5 mmol), potassium acetate (882 g, 9.0 mmol), andPdCl2(dppf)2 (245 mg, 0.3 mmol) using a procedure similar to thatdescribed for compound 0602-107 (Example 34). LCMS: 248 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.34 (s, 12H), 2.97 (s, 6H), 7.19 (m, 2H), 7.26 (m2H).

Step 35b: Ethyl2-(((2-(3-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-108)

The title compound 0603-108 was prepared (245 mg, 91%) as a white solidfrom 0504-54 (224 mg, 0.5 mmol), 0602-108 (490 mg, 2.0 mmol), NaHCO₃(126 mg, 1.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (18mg, 0.025 mmol) in toluene (4 mL), ethanol (2 mL) and water (1 mL) usinga procedure similar to that described for compound 0603-107 (Example30). LCMS: 534 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t, J=6.8 Hz,3H), 2.97 (s, 3H), 3.27 (s, 2H), 3.76 (m, 4H), 3.92 (m, 4H), 4.28 (q,J=6.8 Hz, 2H), 5.23 (s, 2H), 6.85 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.49(s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.79 (br s, 1H), 8.79 (s, 1H).

Step 35c:2-(((2-(3-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 108)

The title compound 108 was prepared (35 mg, 15%) as a yellow solid from0603-108 (130 mg, 0.23 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 172-175° C. LCMS: 521 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 2.96 (s, 3H), 3.23 (s, 2H), 3.75 (m, 4H), 3.91 (m, 4H),5.19 (s, 2H), 6.84 (m, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.70(d, J=7.2 Hz, 1H), 7.75 (br s, 1H), 8.74 (s, 1H), 9.11 (br s, 1H), 11.16(br s, 1H).

Example 36 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 109)

Step 36a: Ethyl2-(methyl((4-morpholino-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-109)

The title compound, 0603-109 was prepared (140 mg, 94%) as a yellowsolid from 0504-54 (135 mg, 0.30 mmol), 3-pyridylboronic acid (41 mg,0.60 mmol), NaHCO₃ (76 mg, 0.90 mmol) and Pd(dppf)₂Cl₂ (11 mg, 0.015mmol) in toluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using aprocedure similar to that described for compound 0603-107 (Example 30).LCMS: 492 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H),3.28 (s, 3H), 3.76 (m, 4H), 3.95 (m, 4H), 5.25 (s, 2H), 7.53 (m, 2H),8.66 (m, 2H), 8.88 (s, 2H), 9.51 (s, 1H).

Step 36b:N-hydroxy-2-(methyl((4-morpholino-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 109)

The title compound 109 was prepared (30 mg, 44%) as a yellow solid from0603-109 (70 mg, 0.14 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). mp: 160-164° C. LCMS: 479 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.24 (s, 3H), 3.77 (s, 4H), 3.94 (s, 4H), 5.21 (s, 2H),7.52 (m, 2H), 8.67 (m, 2H), 8.76 (s, 2H), 9.09 (s, 1H), 9.52 (s, 1H),11.15 (s, H).

Example 37 Preparation of2-(((2-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 110)

Step 37a: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(Compound 0602-110)

The title compound, 0602-110 was prepared (500 mg, 23%) as an oil from2-amino-5-bromopyridine (1.73 g, 10 mmol), bis(pinacolato)diboron (3.81g, 15 mmol), potassium acetate (3 g, 30 mmol), and PdCl₂(dppf)₂ (408 mg,5 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 221 [M+1]⁺. 1H NMR (400 MHz, DMSO-d₆) δ1.25 (s, 12H), 6.30 (s, 2H), 6.39 (d, J=8.0 Hz, 1H), 7.54 (d, J=10.0 Hz,1H), 8.16 (s, 1H).

Step 37b: Ethyl2-(((2-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-110)

The title compound, 0603-110 was prepared (200 mg, 59%) as a white solidfrom 0602-110 (300 mg, 0.67 mmol), 0504-54 (176 mg, 0.8 mmol), NaHCO₃(172 mg, 2 mmol) and bis(triphenylphosphine)palladium(II) chloride (23mg, 0.0335 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL)using a procedure similar to that described for compound 0603-107(Example 30). LCMS: 507 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t,J=6.8 Hz, 3H), 3.29 (s, 3H), 3.81 (m, 4H), 3.95 (m, 4H), 4.28 (m, 2H),5.24 (s, 2H), 6.42 (s, 2H), 6.56 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 8.327(d, J=8.8 Hz,1H), 8.81 (s, 2H), 8.99 (s, 1H), 9.13 (s, 1H), 11.69 (s,1H).

Step 37c:2-(((2-(6-Aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 110)

The title compound 110 was prepared (25 mg, 13%) as a yellow solid from0603-110 (200 mg, 0.4 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 175-181° C. LCMS: 494 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.29 (s, 3H), 3.81 (m, 4H), 3.95 (m, 4H), 5.24 (s, 2H),6.42 (s, 2H), 6.56 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 8.327 (d, J=8.8Hz,1H), 8.81 (s, 2H), 8.99 (s, 1H), 9.13 (s, 1H), 11.195 (s, 1H).

Example 38 Preparation of2-(((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 115)

Step 38a:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(Compound 0602-115)

The title compound, 0602-115 was prepared (120 mg, 11%) as an oil from2-amino-5-bromopyrimidine (865 mg, 5.0 mmol) and bis(pinacolato)diboron(2.54 g, 10 mmol), potassium acetate (1.47 g, 15 mmol), and PdCl₂(dppf)₂(204 mg, 0.25 mmol) using a procedure similar to that described forcompound 0602-107 (Example 34). LCMS: 222 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.26 (s, 12H), 7.04 (s, 2H), 8.37 (s, 2H).

Step 38b: Ethyl2-(((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-115)

The title compound, 0603-115 was prepared (110 mg, 51%) as a white solidfrom 0602-115 (120 mg, 0.54 mmol), 0504-54 (200 mg, 0.45 mmol), NaHCO₃(114 mg, 1.35 mmol), and bis(triphenylphosphine)palladium(II) chloride(16 mg, 0.0225 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL)using a procedure similar to that described for compound 0603-107(Example 30). LCMS: 508 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (t,J=6.8 Hz, 3H), 3.32 (s, 3H), 3.89 (m, 4H), 4.02 (m, 4H), 4.36 (q, J=6.8Hz, 2H), 5.20 (s, 2H), 5.43 (s, 2H), 7.44 (s, 1H), 8.94 (s, 2H), 9.31(s, 2H).

Step 38c:2-(((2-(2-Aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 115)

The title compound 115 was prepared (25 mg, 23%) as a yellow solid from0603-115 (110 mg, 0.2 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 175-181° C. LCMS: 495 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.21 (s, 3H), 3.75 (m, 4H), 3.91 (m, 4H), 5.19 (s, 2H),7.13 (s, 2H), 7.41 (s, 1H), 8.74 (s, 2H), 9.02 (br s, 1H), 9.10 (s, 2H),11.13 (br s, 1H).

Example 39 Preparation ofN-hydroxy-2-(methyl((2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 116)

Step 39a: 5-Bromo-N-methylpyrimidin-2-amine (Compound 0601-116) and5-bromo-N,N-dimethylpyrimidin-2-amine (Compound 0601-117)

A mixture of 5-bromopyrimidin-2-amine (3.48 g, 20 mmol) and DMF (20 mL)was cooled to 0° C. To the mixture NaH (60%, 1.44 g, 36 mmol) was added.After 15 minutes, iodomethane (5 mL, 80 mmol) was added and stirred at0° C. for 0.5 h and the mixture was warmed to room temperature foradditional 4 hours. Water (30 mL) was added and extracted with ethylacetate (3×30 mL). The combined organic layers was washed with brine,dried over Na2SO4, concentrated and purified by column chromatograph onsilica gel (ethyl acetate in petroleum ether, 10% v/v) to give twocompounds: compound 0601-116 (0.76 g, 20%) as a white solid, LCMS: 190[M+2]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 2.75 (d, J=4.8 Hz, 3H), 7.35 (d,J=4.0 Hz, 1H), 8.34 (s, 2H); compound 0601-117 (1.96 g, 49%) as a yellowsolid, LCMS: 202 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 3.12 (s, 6H), 8.43(s, 2H).

Step 39b:N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(Compound 0602-116)

The title compound, 0602-116 was prepared (350 mg, 50%) as yellow solidfrom 5-bromo-N-methylpyrimidin-2-amine (0.56 g, 3 mmol),bis(pinacolato)diboron (1.14 g, 4.5 mmol), potassium acetate (0.88 g, 9mmol), and Pd(dppf)₂Cl₂ (490 mg, 0.6 mmol) using a procedure similar tothat described for compound 0602-107 (Example 34). LCMS: 236 [M+1]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 1.27 (s, 12H), 2.82 (d, J=4.8 Hz, 3H), 7.47(m, 1H), 8.38 (m, 1H), 8.45 (m, 1H).

Step 39c: Ethyl2-(methyl((2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-116)

The title compound, 0603-116 was prepared (100 mg, 64%) as a yellowsolid from 0504-54 (135 mg, 0.30 mmol), 0602-116 (106 mg, 0.45 mmol),NaHCO₃ (76 mg, 0.90 mmol) and Pd(dppf)₂Cl₂ (11 mg, 0.015 mmol) intoluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 522[M+1]⁺; ¹HNMR (400 MHz, CDCl₃) δ 1.39 (t, J=7.2 Hz, 3H), 3.09 (d, J=5.2Hz, 3H), 3.31 (s, 3H), 3.85 (t, J=4.8 Hz, 4H), 3.98 (t, J=4.8 Hz, 4H),4.36 (q, J=7.2 Hz, 2H), 5.19 (s, 2H), 5.47 (d, J=4.8 Hz, 1H), 7.34 (s,1H), 8.93 (s, 2H), 9.26 (s, 2H).

Step 39d:N-hydroxy-2-(methyl((2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 116)

The title compound 116 was prepared (50 mg, 54%) as a yellow solid from0603-116 (96 mg, 0.13 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 183-187° C. LCMS: 509 [M+1]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 2.88 (d, J=4.4 Hz, 3H), 3.23 (s, 3H), 3.74 (s, 4H), 3.90 (s,4H), 5.19 (s, 2H), 7.40 (s, 1H), 7.55 (d, J=4.4 Hz, 1H), 8.75 (s, 2H),9.07 (s, 1H), 9.13 (m, 2H), 11.13 (s, 1H).

Example 40 Preparation of2-(((2-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 117)

Step 40a:N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(Compound 0602-117)

The title compound, 0602-117 was prepared (194 mg, 26%) as yellow solidfrom 5-bromo-N,N-dimethylpyrimidin-2-amine (0.61 g, 3 mmol),bis(pinacolato)diboron (1.14 g, 4.5 mmol), potassium acetate (0.88 g, 9mmol), and Pd(dppf)₂Cl₂ (490 mg, 0.6 mmol) using a procedure similar tothat described for compound 0602-107 (Example 34). LCMS: 168 [M−81]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 1.27 (s, 12H), 3.14 (s, 6H), 8.47 (s, 2H).

Step 40b: Ethyl2-(((2-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(0603-117)

The title compound, 0603-117 was prepared (100 mg, 64%) as a yellowsolid from 0504-54 (135 mg, 0.30 mmol), 0602-117 (112 mg, 0.45 mmol),NaHCO₃ (76 mg, 0.90 mmol) and Pd(dppf)₂Cl₂ (11 mg, 0.015 mmol) intoluene (2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 536[M+1]⁻; ¹HNMR (400 MHz, CDCl₃) δ 1.38 (t, J=7.2 Hz, 3H), 2.37 (s, 6H),3.30 (s, 3H), 3.83 (t, J=4.8 Hz, 4H), 3.97 (t, J=4.8 Hz, 4H), 4.36 (q,J=7.2 Hz, 2H), 5.18 (s, 2H), 7.35 (s, 1H), 8.93 (s, 2H), 9.30 (s, 2H).

Step 40c:2-(((2-(2-(Dimethylamino)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 117)

The title compound 117 was prepared (60 mg, 66%) as a yellow solid from0603-117 (93 mg, 0.17 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 200-206° C. LCMS: 523 [M+1]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 3.18 (d, J=8.8 Hz, 6H), 3.23 (s, 3H), 3.74 (d, J=4.8 Hz, 4H),3.90 (d, J=4.4 Hz, 4H), 5.17 (s, 2H), 7.39 (s, 1H), 8.75 (s, 2H), 9.19(s, 2H).

Example 41 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(pyrimidin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 119)

Step 41a: Ethyl2-(methyl((4-morpholino-2-(pyrimidin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-119)

The title compound, 0603-119 was prepared (160 mg, 46%) as a white solidfrom 0504-54 (314 mg, 0.7 mmol), pyrimidin-2-ylboronic acid (175 mg, 1.4mmol), NaHCO₃ (176 mg, 2.1 mmol) andbis(triphenylphosphine)palladium(II) chloride (24 mg, 0.03 mmol) intoluene (8 mL), ethanol (5 mL) and water (3 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 493[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.35 (t, J=7.2 Hz, 3H), 3.31 (d,J=8.4 Hz, 3H), 3.76 (m, 4H), 3.92 (m, 4H), 4.33 (q, J=6.8 Hz, 2H), 5.28(d, J=12.0 Hz, 2H), 7.47 (s, 0.5H), 7.59 (s, 0.5H), 8.53 (s, 0.5H), 8.92(d, J=6.0 Hz, 2H), 9.34 (s, 0.5H), 9.67 (s, 1H).

Step 41b:N-hydroxy-2-(methyl((4-morpholino-2-(pyrimidin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 119)

The title compound 119 was prepared (60 mg, 40%) as a white solid from0603-119 (150 mg, 0.3 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 159-160° C. LCMS: 480 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 3.40 (s, 3H), 3.92 (m, 4H), 4.13 (m, 4H), 5.19 (s, 2H), 6.84(m, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.70 (d, J=7.2 Hz, 1H),7.75 (br s, 1H), 8.74 (s, 1H), 9.11 (br s, 1H), 11.16 (br s, 1H).

Example 42 Preparation ofN-hydroxy-2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 120)

Step 42a: 5-Bromo-2-methylpyrimidine (Compound 0601-120)

Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) toprepare sodium ethoxide solution in ethanol. The above freshly preparedsodium ethoxide in ethanol solution (3.5 mL) was added to a stirredsuspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixturewas warmed to 50° C., then the heating bath was removed and a solutionof mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at arate which maintained a constant temperature, followed by a furthersodium ethoxide in ethanol solution (2 mL). After cooling, the mixturewas filtered and evaporated to a residue which was shaken vigorouslywith hydrochloric acid (2 M×2.4 mL). The brown precipitate was filteredand washed with cold water, then freeze-dried to give5-bromo-2-methylpyrimidine-4-carboxylic acid (350 mg, 42%) as a brownsolid. LCMS: 218 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 2.62 (s, 3H), 9.03(s, 1H).

A mixture of compound 5-bromo-2-methylpyrimidine-4-carboxylic acid (350mg, 1.6 mmol) in xylene (5 mL) was refluxed for 2 h. After cooling, themixture was applied directly to a silica column, which was eluted withpetroleum ether, then ethyl acetate in petroleum ether (5% v/v) to givecompound 0601-120 (170 mg, 61%) as a white solid. LCMS: 173 [M+1]⁺, ¹HNMR (400 MHz, DMSO-d₆): δ 2.59 (s, 3H), 8.87 (s, 2H).

Step 42b:2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(Compound 0602-120)

The title compound, 0602-120 was prepared (100 mg, 52%) as a yellow oilfrom 0601-120 (150 mg, 0.87 mmol), bis(pinacolato)diboron (331 mg, 1.3mmol), PdCl₂(dppf)₂ (21 mg, 0.026 mmol) and dried potassium acetate (256mg, 2.62 mmol)using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 221 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.32 (s, 12H), 2.64 (s, 3H), 8.81 (s, 2H).

Step 42c: Ethyl2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-120)

The title compound, 0603-120 was prepared (210 mg, 74%) as a off-whitesolid from 0504-54 (250 mg, 0.56 mmol), 0602-120 (880 mg, 4 mmol),sodium hydrogen carbonate (168 mg, 2 mmol), andbis(triphenylphosphine)palladium(II) chloride (23 mg, 0.03 mmol) intoluene (8 mL), ethanol (5mL) and water (2 mL) using a procedure similarto that described for compound 0603-107 (Example 30). LCMS: 507 [M+1]⁺;¹H NMR (400 MHz, CDCl₃): δ 1.31 (t, J=7.2 Hz, 3H), 2.74 (s, 3H), 3.25(s, 3H), 3.79 (t, J=4.4 Hz, 4H), 3.94 (t, J=4.4 Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.14 (s, 2H), 7.32 (s, 1H), 8.86 (s, 2H), 9.48 (s, 2H).

Step 42d:N-hydroxy-2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 120)

The title compound 120 was prepared (150 mg, 73%) as a white solid from0603-120 (210 mg, 0.41 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 184-186° C. LCMS: 494 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 2.69 (s, 3H), 3.24 (s, 3H), 3.76 (t, J=4.4 Hz, 4H), 3.94 (t,J=4.4 Hz, 4H), 5.21 (s, 2H), 7.49 (s, 1H), 8.76 (s, 2H), 9.06 (s, 1H),9.9.48 (s, 2H), 11.14 (s, 1H).

Example 43 Preparation of2-(((2-(2-ethylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 121)

Step 43a: 5-Bromo-2-ethylpyrimidine (0601-121)

After dissolving propionitrile (38 g, 0.69 mol) in anhydrous ethanol(100 mL), HCl gas was bubbled in at 0° C. for 4 h. The mixture wasstirred overnight at room temperature and the excess HCl gas and ethanolwere removed in vacuum. Ether (100 mL) was added in and the solidsubstance were filtered and washed with ether (100 mL). The solid wasdried and then dissolved in ethanol (100 mL) and NH₃ gas was bubbled inat 0° C. for an hour, the solution was filtered and the filtrate wasconcentrated to half of the original volume, the solid was filtered off.The solid substance thus obtained was filtered off again and thefiltrate was concentrated to give propionimidamide hydrochloride (34 g,45%) as a white solid. GCMS: 71 [M−1]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ1.17 (t, J=7.6 Hz, 3H), 2.40 (q, J=7.6 Hz, 2H), 8.79 (s, 2H), 9.09 (s,2H).

Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) toprepare sodium ethoxide solution in ethanol. The above freshly preparedethanol solution (3.5 mL) was added to a stirred suspension ofpropionimidamide hydrochloride (1.05 g, 9.69 mmol). The mixture waswarmed to 55° C., then the heating bath was removed and a solution ofmucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a ratewhich maintained a constant temperature, followed by a further sodiumethoxide solution (2 mL). After cooling, the mixture was filtered andevaporated to a residue which was shaken vigorously with hydrochloricacid (2 M×2.4 mL). The brown precipitate was filtered off and washedwith cold water, then freeze-dried to give5-Bromo-2-ethylpyrimidine-4-carboxylic acid (330 mg, 37%) as a yellowsolid. LCMS: 231 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆): δ 1.25 (t, J=7.6 Hz,3H), 2.88 (q, J=7.6 Hz, 2H), 9.05 (s, 1H).

A mixture of 5-Bromo-2-ethylpyrimidine-4-carboxylic acid (5.6 g, 24.3mmol) in xylene (50 mL) was refluxed for 2 h. After cooling, the mixturewas applied directly to a silica column, which was eluted with petroleumether, then ethyl acetate in petroleum ether (5%) to give compound0601-121 (1.7 g, 38%) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d₆):1.26 (t, J=7.6 Hz, 3H), 2.87 (q, J=7.6 Hz, 2H), 8.90 (s, 2H).

Step 43b:2-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(Compound 0602-121)

The title compound, 0602-121 was prepared (crude 3.7 g) as a yellow oilfrom 0601-121 (1.7 g, 9.1 mmol), bis(pinacolato)diboron (3.5 g, 13.6mmol), PdCl₂(dppf)₂ (222 mg, 0.27 mmol) and potassium acetate (2.7 g, 27mmol) using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 235 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.27 (t,J=7.6 Hz, 3H), 1.32 (s, 12H), 2.91 (q, J=7.6 Hz, 2H), 8.84 (s, 2H).

Step 43c: Ethyl2-(((2-(2-ethylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-121)

The title compound, 0603-121 was prepared (120 mg, 41%) as a yellowsolid from 0504-54 (250 mg, 0.56 mmol), 0602-121 (3.7 g, crude), sodiumhydrogen carbonate (168 mg, 2 mmol) andbis(triphenylphosphine)palladium(II) chloride (23 mg, 0.03 mmol) intoluene (8 mL), ethanol (5mL) and water (2 mL) using a procedure similarto that described for compound 0603-107 (Example 30). LCMS: 521 [M+1]⁺;¹H NMR (400 MHz, CDCl₃): δ 1.29-1.36 (m, 6H), 3.00 (q, J=8 Hz, 2H), 3.25(s, 3H), 3.79 (t, J=4.4 Hz, 4H), 3.94 (t, J=4.4 Hz, 4H), 4.29 (q, J=7.2Hz, 2H), 5.14 (s, 2H), 7.32 (s, 1H), 8.86 (s, 2H), 9.51 (s, 2H).

Step 43d:N-Hydroxy-2-(methyl((2-(2-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 121)

The title compound 121 was prepared (66 mg, 56%) as a white solid from0603-121 (120 mg, 0.23 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 153-156° C. LCMS: 508 [M+1]⁻; ¹H NMR (400 MHz,DMSO-d₆): δ 1.32 (t, J=7.2 Hz, 3H), 2.97 (q, J=7.2 Hz, 2H), 3.24 (s,3H), 3.76 (t, J=4.4 Hz, 4H), 3.95 (t, J=4.4 Hz, 4H), 5.21 (s, 2H), 7.49(s, 1H), 8.75 (s, 2H), 9.06 (s, 1H), 9.52 (s, 2H), 11.13 (s, 1H).

Example 44 Preparation of2-(((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 125)

Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)

A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g,40.3 mmol) in chloroform (100 mL) was stirred for 2 h at roomtemperature, then the solvent was removed in vacuum. Water (100 mL) wasadded and stirred for 30 min at room temperature, filtered. The solidwas washed with water and dried to get compound 0601-125 (6.3 g, 91%) asa white solid. LCMS: 188 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 2.32 (s,3H), 6.79 (s, 2H), 8.21 (s, 1H).

Step 44b:4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(Compound 0602-125)

The title compound, 0602-125 was prepared (430 mg, 69%) as a grey solidfrom 0601-125 (500 mg, 2.66 mmol), bis(pinacolato)diboron (1.01 g, 4.0mmol), PdCl₂(dppf)₂ (217.2 mg, 0.27 mmol), potassium acetate (783 mg,7.98 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 236 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ1.27 (s, 12H), 2.37 (s, 3H), 6.89 (s, 2H), 8.30 (s, 1H).

Step 44c: Ethyl2-(((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-125)

The title compound, 0603-125 was prepared (160 mg, 55%) as a white solidfrom 0504-54 (376 mg, 0.84 mmol), 0602-125 (130 mg, 0.56 mmol), CsF (256mg, 1.68 mmol) and bis(triphenylphosphine)palladium(II) chloride (59 mg,0.084 mmol) in 1,4-dioxane (5 mL) and water (1 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 522[M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.38 (d, J=7.2 Hz, 3H), 2.73 (s, 3H),3.31 (s, 3H), 3.84 (m, 4H), 3.96 (m, 4H), 4.37 (q, J=7.2 Hz, 2H), 5.20(s, 2H), 5.23 (s, 2H), 7.35 (s, 1H), 8.89 (s, 1H), 8.93 (s, 2H).

Step 44d:2-(((2-(2-Amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 125)

The title compound 125 was prepared (92 mg, 62%) as a white solid from0603-125 (150 mg, 0.29 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 195-198° C. LCMS: 509 [M+1]⁻; ¹H NMR (400MHz, DMSO-d₆) δ 2.62 (s, 3H), 3.23 (s, 3H), 3.74 (m, 4H), 3.86 (m, 4H),5.20 (s, 2H), 6.86 (s, 2H), 7.42 (s, 1H), 8.77 (s, 2H), 8.81 (s, 1H),9.10 (s, 1H), 11.21 (s, 1H).

Example 45 Preparation ofN-hydroxy-2-(((2-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 130)

Step 45a: 2-(3-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Compound 0602-130)

The title compound, 0602-130 was prepared (800 mg, 68%) as an oil from1-bromo-methoxybenzene (930 mg, 5.0 mmol), bis(pinacolato)diboron (2.54g, 10 mmol), potassium acetate (1.47 g, 15 mmol), and PdCl₂(dppf)₂ (204mg, 0.25 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 235 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.34 (s, 12H), 3.83 (s, 3H), 7.0 (d, J=6.4 Hz, 2H), 7.29 (m, 2H), 7.41(d, J=5.6 Hz, 1H).

Step 45b: Ethyl2-(((2-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-130)

The title compound, 0603-130 was prepared (120 mg, 51%) as a white solidfrom 0602-130 (126 mg, 0.54 mmol), 0504-54 (200 mg, 0.45 mmol), NaHCO₃(114 mg, 1.35 mmol), and bis(triphenylphosphine)palladium(II) chloride(16 mg, 0.0225 mmol) in toluene (8 mL), ethanol (5 mL), and water (2 mL)using a procedure similar to that described for compound 0603-107(Example 30). LCMS: 521 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t,J=6.8 Hz, 3H), 3.27 (s, 3H), 3.76 (m, 4H), 3.83 (s, 3H), 3.92 (m, 4H),3.94 (s, 2H), 4.29 (q, J=6.8 Hz, 2H), 5.23 (s, 2H), 7.06 (d, J=7.2 Hz1H), 7.39 (t, J=10.4 Hz, 1H), 7.49 (s, 1H), 7.92 (s, 1H), 7.99 (d, J=8Hz,1H), 8.82 (s, 1H).

Step 45c:N-hydroxy-2-(((2-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 130)

The title compound 130 was prepared (15 mg, 15%) as a yellow solid from0603-130 (110 mg, 0.2 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 179-181° C. LCMS: 508 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.77 (m, 4H), 3.83 (s, 3H), 3.93 (m, 4H),5.21 (s, 2H), 7.07 (d, J=9.2 Hz, 1H), 7.39 (t, J=10.4 Hz, 1H), 7.42 (s,1H), 7.91 (s, 1H), 8.0 (d, J=16.4 Hz, 1H), 8.75 (s, 2H), 9.02 (br s,1H), 11.14 (br s, 1H).

Example 46 Preparation ofN-hydroxy-2-(((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 132)

Step 46a: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(Compound 0602-132)

The title compound, 0602-132 was prepared (600 mg, 68%) as an oil from3-bromophenol (700 mg, 4.0 mmol), bis(pinacolato)diboron (1.5 g, 6mmol), potassium acetate (1.2 g, 12 mmol), and PdCl2(dppf)2 (163 mg, 0.2mmol) using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 221 [M+1]⁺. 1H NMR (400 MHz, CDCl₃) δ 1.34 (s, 12H),5.37 (s, 1H), 6.96 (d, J=4.0 Hz, 1H), 7.26 (m, 2H), 7.36 (d, J=7.2 Hz,1H).

Step 46b: Ethyl2-(((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-132)

The title compound, 0603-132 was prepared (160 mg, 47%) as a white solidfrom 0602-132 (300 mg, 0.67 mmol), 0504-54 (176 mg, 0.8 mmol), NaHCO₃(172 mg, 2 mmol), and bis(triphenylphosphine)palladium(II) chloride (23mg, 0.0335 mmol) in toluene (8 mL), ethanol (5 mL) and water (2 mL)using a procedure similar to that described for compound 0603-107(Example 30). LCMS: 507 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t,J=6.8 Hz, 3H), 3.27 (s, 3H), 3.76 (m, 4H), 3.92 (m, 4H), 4.29 (q, J=6.8Hz, 2H), 5.24 (s, 2H), 6.84 (d, J=16.8 Hz, 2H), 7.24 (t, J=8 Hz, 1H),7.48 (s, 1H), 7.83 (m, 2H), 8.88 (s, 2H), 9.49 (s, 1H).

Step 46c:N-hydroxy-2-(((2-(3-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 132)

The title compound 132 was prepared (53 mg, 34%) as a yellow solid from0603-132 (160 mg, 0.32 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 175-181° C. LCMS: 494 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.76 (m, 4H), 3.92 (m, 4H), 5.19 (s, 2H),6.85 (d, J=10.4 Hz, 1H), 7.24 (t, J=6.8 Hz, 1H), 7.44 (s, 1H), 7.82 (m,2H), 8.74 (s, 2H), 9.51 (br s, 1H).

Example 47 Preparation of2-(((2-(3-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 134)

Step 47a:Ethyl-2-(((2-(3-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-134)

To the solution of 0603-107 (170 mg, 0.31 mmol) in THF (10 mL) was addedaqueous HCl solution (6M, 10 mL) at 50° C. and the mixture was stirredfor 2 hours at this temperature. The reaction mixture was neutralizedwith saturated aqueous NaHCO₃ and extracted with ethyl acetate. Theseparated organic layer was washed with water, brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the titlecompound 0603-134 (130 mg, 83%) as a white solid. LCMS: 506 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=7.6 Hz, 3H), 3.27 (s, 3H), 3.40 (s,2H), 3.76 (t, J=5.2 Hz, 4H), 3.93 (t, J=4.8 Hz, 4H), 7.89 (q, J=7.6 Hz,2H), 5.24 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.47(s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 8.88 (s, 1H).

Step 47b:2-(((2-(3-Aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 134)

The title compound 134 was prepared (35 mg, 28%) as a white solid from0603-134 (130 mg, 0.25 mmol) and freshly prepared hydroxylamine methanolsolution (4 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 179-182° C. LCMS: 493 [M+1]⁻; ¹H NMR (400 MHz,DMSO-d₆):δ 3.24 (s, 3H), 3.77 (t, J=4.0 Hz, 4H), 3.96 (t, J=4.0 Hz, 4H),5.22 (s, 2H), 6.98 (d, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.47 (s,1H), 7.86 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 8.76 (s, 2H), 9.07 (s, 1H),11.15 (s, 1H).

Example 48 Preparation of2-(((2-(4-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 135)

Step 48a: N-(4-bromobenzyl)acetamide (Compound 0601-135)

To the solution of 4-bromobenzylamine hydrochloride (1.2 g, 5.4 mmol)and Et₃N (5.5 g, 54 mmol) in dichloromethane (10 mL) was added CH₃COCl(555 mg, 7.02 mmol) at 0° C. and stirred for 2 hr at 30° C. Then themixture was concentrated and the residue was dissolved in CH₂Cl₂ (30mL), washed with water, dried over Na₂SO₄ and concentrated to obtain0601-135 (1.3 g, 100%) as a yellow solid. LCMS: 228 [M+1]⁺, ¹H NMR (400MHz, DMSO-d₆) δ 2.00 (s, 3H), 4.33 (d, J=6.4 Hz, 2H), 6.26 (s, 1H), 7.13(d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H).

Step 48b:N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide(Compound 0602-135)

The title compound, 0602-135 was prepared (825 mg, 60%) as a yellowsolid from 0601-135 (1.2 g, 5 mmol), bis(pinacolato)diboron (1.9 g, 7.5mmol), potassium acetate (1.47 g, 15 mmol), and Pd(dppf)₂Cl₂ (410 mg,0.5 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 276 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ1.27 (s, 12H), 1.87 (s, 3H), 4.26 (d, J=6.0 Hz, 2H), 7.25 (d, J=8.0 Hz,2H), 7.62 (d, J=8.0 Hz, 2H), 8.36 (t, J=5.6 Hz, 1H).

Step 48c: Methyl2-(((2-(4-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-135)

A mixture of compound 0602-135 (200 mg, 0.73 mmol), 0504-54 (261 mg,0.58 mmol), NaHCO₃ (184 mg, 2.2 mmol) andbis(triphenylphosphine)palladium(II) chloride (52 mg, 0.073 mmol) intoluene (4 mL), ethanol (2 mL) and water (0.5 mL) was flushed withnitrogen and heated under microwave irradiation at 130° C. for 2 h. Thereaction mixture was partitioned between dichloromethane and water,organic layer was washed with brine, dried over Na₂SO₄, filtered andevaporated in vacuum. The resulting residue was purified by columnchromatography (methanol in dichloromethane, 2-5% v/v) to give ethyl2-(((2-(4-(acetamidomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(300 mg, 92%) as a white solid. LCMS: 562 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 1.36 (m, 3H), 1.96 (s, 3H), 3.33 (s, 3H), 3.83 (m, 4H), 3.94(m, 4H), 4.36 (m, 4H), 5.29 (s, 2H), 7.41 (d, J=7.6 Hz, 2H), 7.54 (s,1H), 8.39 (d, J=8.0 Hz, 2H), 8.47 (m, 1H), 8.94 (s, 2H).

The above ethyl ester (250 mg, 0.45 mmol) was dissolved in THF (8 mL),then aqueous HCl solution (6M, 12 mL) was added and stirred for 12 hr at85° C. Then the mixture was adjusted pH 4 with NaOH at 0° C., filteredand washed with CH₂Cl₂ to get2-(((2-(4-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylicacid (200 mg, 91%) as a white solid. The solid was directly used in nextstep without further purification. LC-MS: 492 [M+1]⁺.

The above acid (230 mg, 0.47 mmol) was dissolved in MeOH (10 mL). SOCl₂(5 mL) was added to above solution at 0° C. and stirred for 1.5 hr atreflux. Then the mixture was concentrated, added water, adjusted to pH8with saturated aqueous NaHCO₃ solution, extracted with CH₂Cl₂ andevaporated in vacuum to get compound 0603-135 (210 mg, 88%) as a yellowsolid. LC-MS: 506 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.28 (s, 3H), 3.83(m, 9H), 3.97 (m, 4H), 5.20 (m, 2H), 7.38 (m, 3H), 8.34 (m, 2H), 8.86(m, 2H).

Step 48d:2-(((2-(4-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 135)

The title compound 135 was prepared (60 mg, 30%) as a light yellow solidfrom 0603-135 (200 mg, 0.40 mmol) and freshly prepared hydroxylaminemethanol solution (20 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 184-186° C. LCMS: 507 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.76 (m, 4H), 3.93 (m, 6H), 5.20 (s,2H), 7.45 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 8.36 (d, J=8.0 Hz, 2H), 8.75(s, 2H).

Example 49 Preparation of2-(((2-(3-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 137)

Step 49a: N-(3-bromobenzyl)acetamide (Compound 0601-137)

To the solution of 3-bromobenzylamine hydrochloride (1.2 g, 5.4 mmol)and Et₃N (5.5 g, 54 mmol) in CH₂Cl₂ (10 mL) was added CH₃COCl (555 mg,7.02 mmol) at 0° C. and stirred for 2 hr at 30° C. Then the mixture wasconcentrated and the residue was dissolved in CH₂Cl₂, washed with water,dried over Na₂SO₄, and concentrated to obtain 0601-137 (1.2 g, 98%) as ayellow solid. LCMS: 228 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.88 (s,3H), 4.25 (d, J=6.0 Hz, 2H), 7.28 (m, 2H), 7.43 (m, 2H), 8.39 (s, 1H).

Step 49b:N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide(Compound 0602-137)

The title compound, 0602-137 was prepared (1.0 g, 72%) as a yellow solidfrom 0601-137 (1.2 g, 5 mmol), bis(pinacolato)diboron (1.9 g, 7.5 mmol),potassium acetate (1.47 g, 15 mmol), and Pd(dppf)₂Cl₂ (410 mg, 0.5 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 276 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 1.28 (s,12H), 1.85 (s, 3H), 4.23 (d, J=6.0 Hz, 2H), 7.33 (m, 2H), 7.54 (d, J=7.2Hz, 1H), 7.57 (s, 1H), 8.35 (t, J=5.6 Hz, 1H).

Step 49c: Methyl2-(((2-(3-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate (Compound 0603-137)

A mixture of 0602-137 (400 mg, 1.46 mmol), 0504-54 (522 mg, 1.16 mmol),NaHCO₃ (368 mg, 4.4 mmol), and bis(triphenylphosphine)palladium(II)chloride (104 mg, 0.146 mmol) in toluene (4 mL), ethanol (2 mL) andwater (0.5 mL) was flushed with nitrogen and heated under microwaveirradiation at 130° C. for 2 h. The reaction mixture was partitionedbetween dichloromethane and water, organic layer was washed with brine,dried over Na₂SO₄, filtered and evaporated in vacuum. The resultingresidue was purified by column chromatography (methanol indichloromethane, 2-5% v/v) to give ethyl2-(((2-(3-(acetamidomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(580 mg, 89%) as a white solid. LCMS: 562 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 1.28 (m, 3H), 1.88 (s, 3H), 3.27 (s, 3H), 3.76 (m, 4H), 3.92(m, 4H), 4.27 (m, 4H), 5.23 (s, 2H), 7.38 (m, 2H), 7.49 (m, 1H), 8.30(m, 2H), 8.43 (m, 1H), 8.87 (s, 2H).

The above ethyl ester (300 mg, 0.53 mmol) was dissolved in THF (8 mL),then aqueous HCl solution (6M, 12 mL) was added and stirred for 12 hr at85° C. Then the above mixture was adjusted pH 4 with NaOH at 0° C.,filtered and washed by CH₂Cl₂ to get2-(((2-(3-(Aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylicacid (245 mg, 93%) as a white solid. LC-MS: 492 [M+1]⁺.

The acid (300 mg, 0.61 mmol) was dissolved in MeOH (10 mL). SOCl₂ (5 mL)was added to above solution at 0° C. and stirred for 1.5 hr at reflux.Then the mixture was concentrated, added water, adjusted PH 8 withNaHCO₃, extracted with CH₂Cl₂ and evaporated in vacuum to get compound0603-137 (260 mg, 84%) as a yellow solid. LC-MS: 506 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.27 (s, 3H), 3.76 (m, 4H), 3.82 (s, 3H), 3.95 (m, 6H),5.24 (s, 2H), 7.45 (m, 3H), 8.31 (m, 1H), 8.41 (s, 1H), 8.88 (m, 2H).

Step 49d:2-(((2-(3-(aminomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 137)

The title compound 137 was prepared (46 mg, 18%) as a light yellow solidfrom 0603-137 (250 mg, 0.5 mmol) and freshly prepared hydroxylaminemethanol solution (20 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 173-176° C. LCMS: 507 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.76 (m, 4H), 3.94 (m, 4H), 3.99 (s,2H), 5.20 (s, 2H), 7.45 (s, 1H), 7.50 (m, 2H), 8.32 (m, 1H), 8.38 (s,2H), 8.43 (s, 1H), 8.75 (s, 2H).

Example 50 Preparation ofN-hydroxy-2-(((2-(3-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 138)

Step 50a:(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(Compound 0602-138)

The title compound, 0602-138 was prepared (300 mg, 43%) as a yellow oilfrom m-bromobenzyl alcohol (0.56 g, 3 mmol), bis(pinacolato)diboron(1.14 g, 4.5 mmol), potassium acetate (1.32 g, 9 mmol), and Pd(dppf)₂Cl₂(490 mg, 0.6 mmol) using a procedure similar to that described forcompound 0602-107 (Example 34). LCMS: 252 [M+18]⁺; ¹HNMR (400 MHz,CDCl₃) δ 1.35 (s, 12H), 1.66 (s, 1H), 4.70 (s, 2H), 7.38 (t, J=7.2 Hz,1H), 7.49 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.80 (s, 1H).

Step 50b: Ethyl2-(((2-(3-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(0603-138)

The title compound, 0603-138 was prepared (140 mg, 90%) as a white solidfrom 0504-54 (135 mg, 0.30 mmol), 0602-138 (105 mg, 0.45 mmol), NaHCO₃(76 mg, 0.90 mmol), and Pd(dppf)₂Cl₂ (11 mg, 0.015 mmol) in toluene (2.5mL), ethanol (1.6 mL), and water (0.7 mL) using a procedure similar tothat described for compound 0603-107 (Example 30). LCMS: 521 [M+1]⁻;¹HNMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 3.27 (s, 3H), 3.77(m, 4H), 3.93 (q, J=7.2 Hz, 2H), 4.59 (d, J=6.0 Hz, 2H), 5.24 (s, 2H),5.29 (t, J=5.6 Hz, 1H), 7.43 (m, 2H), 7.50 (s, 1H), 8.26 (m, 1H), 8.37(s, 1H), 8.88 (s, 2H).

Step 50c:N-hydroxy-2-(((2-(3-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 138)

The title compound 138 was prepared (30 mg, 44%) as a light yellow solidfrom 0603-138 (70 mg, 0.13 mmol) and freshly prepared hydroxylaminemethanol solution (10 mL) using a procedure similar to that describedfor compound 3 (Example 1). mp 160-164° C. LCMS: 508 [M+1]⁺; ¹HNMR (400MHz, DMSO-d₆) δ 3.24 (s, 3H), 3.77 (s, 4H), 3.94 (s, 2H), 4.59 (d, J=5.6Hz, 2H), 5.21 (s, 2H), 5.28 (t, J=5.6 Hz, 1H), 7.44 (m, 3H), 8.27 (m,1H), 8.37 (s, 1H), 8.75 (s, 2H), 9.07 (s, 1H).

Example 51 Preparation ofN-hydroxy-2-(((2-(3-(methoxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 139)

Step 51a: 1-Bromo-3-(methoxymethyl)benzene (Compound 0601-139)

To a solution of m-bromobenzyl alcohol (1.0 g, 5.3 mmol) in THF (10 mL)was added NaH (0.26 g, 10.6 mmol) at 0° C., stirred for 10 minutes,followed by addition of iodomethane (1.1 g, 7.9 mmol). The resultingreaction mixture was stirred for 1 hour. To the mixture ethyl acetate(30 mL) was added, washed with water, brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the titlecompound 0601-139 (1.0 g, 93%) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ3.30 (s, 3H), 4.41 (s, 2H), 7.29 (t, J=8.0 Hz, 1H), 7.40 (t, J=7.6 Hz,1H), 7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H).

Step 51b:2-(3-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Compound 0602-139)

The title compound, 0602-139 was prepared (1.2 g, 97%) as an oil from0601-139 (1.1 g, 5.4 mmol), bis(pinacolato)diboron (2.1 g, 8.1 mmol),potassium acetate (1.6 g, 16.3 mmol), and PdCl₂(dppf)₂ (45 mg, 0.05mmol) using a procedure similar to that described for compound 0602-107(Example 34). ¹H NMR (400 MHz, DMSO-d₆) δ 1.28 (s, 12H), 3.28 (s, 3H),4.40 (s, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.58 (d,J=7.2 Hz, 1H), 7.63 (s, 1H).

Step 51c:Ethyl-2-(((2-(3-(methoxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-139)

The title compound, 0603-139 was prepared (180 mg, 71%) as a white solidfrom 0504-54 (210 mg, 0.46 mmol), 0602-139 (174 mg, 0.7 mmol), sodiumhydrogen carbonate (118 mg, 1.4 mmol), andbis(triphenylphosphine)palladium(II) chloride (16 mg, 0.02 mmol) intoluene (8 mL), ethanol (2 mL), and water (1 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 535[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t, J=7.2 Hz, 3H), 3.27 (s,3H), 3.33 (s, 3H), 3.76 (m, 4H), 3.93 (m, 4H), 4.28 (q, J=7.2 Hz, 2H),4.50 (s, 2H), 5.23 (s, 2H), 7.45 (q, J=7.2 Hz, 1H), 7.49 (s, 1H), 8.31(d, J=7.6 Hz, 1H), 8.34 (s, 1H), 8.87 (m, 2H).

Step 51d:N-hydroxy-2-(((2-(3-(methoxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 139)

The title compound 139 was prepared (56 mg, 47%) as an orange solid from0603-139 (120 mg, 0.22 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 178-181° C. LCMS: 522 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆):δ 3.24 (s, 3H), 3.33 (s, 3H), 3.77 (m, 4H), 3.93 (m, 4H), 4.51(s, 2H), 5.21 (s, 2H), 7.43 (q, J=7.6 Hz, 2H), 7.47 (s, 1H), 8.31 (d,J=7.2 Hz, 1H), 8.34 (s, 1H), 8.75 (s, 2H), 9.05 (s, 1H), 11.12 (s, 1H).

Example 52 Preparation ofN-hydroxy-2-(((2-(4-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 140)

Step 52a:(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(Compound 0602-140)

The title compound, 0602-140 was prepared (670 mg, 94%) as an oil from(4-bromophenyl)methanol (0.56 g, 3 mmol), bis(pinacolato)diboron (1.14g, 4.5 mmol), potassium acetate (1.32 g, 9 mmol), and PdCl₂(dppf)₂ (490mg, 0.6 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 217 [M-OH]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ1.28 (s, 12H), 4.51 (d, J=5.6 Hz 2H), 5.23 (t, J=6.0 Hz, 1H), 7.32 (d,J=8.0 Hz, 2H), 7.62 (d, J=7.6 Hz, 2H).

Step 52b: Ethyl2-(((2-(4-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-140)

The title compound, 0603-140 was prepared (120 mg, 77%) as a white solidfrom 0504-54 (135 mg, 0.30 mmol), 0602-140 (105 mg, 0.45 mmol), NaHCO₃(76 mg, 0.90 mmol), and (PPh₃)PdCl₂ (11 mg, 0.015 mmol) in toluene (2.5mL), ethanol (1.6 mL), and water (0.7 mL) using a procedure similar tothat described for compound 0603-107 (Example 30). LCMS: 521 [M+1]⁻;¹HNMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 3.25 (s, 3H), 3.74(t, J=4.4 Hz, 4H), 3.90 (t, J=7.2 Hz, 4H), 4.26 (q, J=7.2 Hz, 2H), 4.56(d, J=6.4 Hz, 2H), 5.21 (s, 2H), 5.26 (t, J=5.6 Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 7.46 (s, 1H), 8.34 (d, J=8.8 Hz, 2H), 8.85 (s, 2H).

Step 52c:N-Hydroxy-2-(((2-(4-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 140)

The title compound 140 was prepared (61 mg, 63%) as a yellow solid from0603-140 (100 mg, 0.19 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 218-223° C. LCMS: 508 [M+1]⁺; ¹HNMR (400MHz, DMSO-d6) δ 3.23 (s, 3H), 3.76 (d, J=4.4 Hz, 4H), 3.91 (d, J=4.0 Hz,4H), 4.56 (d, J=4.8 Hz, 2H), 5.19 (s, 2H), 5.27 (t, J=5.6 Hz, 1H), 7.42(t, J=8.8 Hz, 3H), 8.34 (d, J=8.0 Hz, 2H), 8.74 (s, 2H), 9.08 (s, 1H),11.13 (s, 1H).

Example 53 Preparation ofN-hydroxy-2-(((2-(2-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 141)

Step 53a: 2-Bromobenzyl acetate (Compound 0601-141)

To a solution of o-bromobenzyl alcohol (2.0 g, 10.7 mmol) in CH₂Cl₂ (20mL) was added acetyl chloride (1.1 g, 13.9 mmol) and TEA (2.16 g, 21.4mmol) at 0° C., then stirred for 2 hours. The reaction mixture waswashed with water, brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give the title compound 0601-141 (2.4 g, 97%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.09 (s, 3H), 5.10 (s,2H), 7.29 (t, J=8.0 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 7.64 (d, J=8.0 Hz, 1H).

Step 53b: 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate(Compound 0602-141)

The title compound, 0602-141 was prepared (2.3 g, 80%) as an oil from0601-141 (2.4 g, 10.5 mmol), bis(pinacolato)diboron (4.1 g, 16.3 mmol),potassium acetate (3.2 g, 32.7 mmol), and PdCl₂(dppf)₂ (89 mg, 0.11mmol) using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 277 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.28 (s,12H), 2.03 (s, 3H), 5.23 (s, 2H), 7.34 (t, J=7.2 Hz, 1H), 7.37 (d, J=7.2Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H).

Step 53c: Ethyl2-(((2-(2-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-141)

The title compound, 0603-141 was prepared (80 mg, 17%) as a white solidfrom 0504-54 (420 mg, 0.92 mmol), 0602-141 (386 mg, 1.4 mmol), sodiumhydrogen carbonate (236 mg, 2.8 mmol), andbis(triphenylphosphine)palladium(II) chloride (32 mg, 0.04 mmol) intoluene (8 mL), ethanol (4 mL), and water (2 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 521[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H), 3.26 (s,3H), 3.74 (m, 4H), 3.88 (m, 4H), 4.28 (q, J=6.8 Hz, 2H), 4.75 (d, J=6.0Hz, 2H), 5.24 (s, 2H), 5.44 (t, J=6.0 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H),7.44 (t, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.62 (m, 1H), 7.92 (d, J=6.8 Hz,1H), 8.87 (s, 1H).

Step 53d:N-hydroxy-2-(((2-(2-(hydroxymethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 141)

The title compound 141 was prepared (58 mg, 37%) as a yellow solid from0603-141 (160 mg, 0.3 mmol) and freshly prepared hydroxylamine methanolsolution (4 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 173-176° C. LCMS: 508 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆):δ 3.23 (s, 3H), 3.73 (m, 4H), 3.88 (m, 4H), 4.75 (d, J=6.0 Hz,2H), 5.20 (s, 2H), 5.45 (t, J=6.0 Hz, 1H), 7.35 (t, J=6.8 Hz, 1H), 7.42(d, J=7.6 Hz, 1H), 7.46 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 8.74 (s, 2H), 9.05 (s, 1H), 11.12 (s, 1H).

Example 54 Preparation of2-(((2-(3-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 142)

Step 54a: 3-Bromobenzamide (Compound 0601-142)

To a solution of m-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) wasadded 30% H₂O₂ (5 g, 13 mmol) and K₂CO₃ at 0° C., and stirred at roomtemperature for 30 min. The mixture was poured into water and filtered,the solid was washed with water, dried to got the compound 0601-142 (1.8g, 82%) as a white solid. LCMS: 200 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.41 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J_(1,2)=8.0, 0.8 Hz,1H), 7.85 (d, J=8.0 Hz, 1H), 8.03 (t, J=1.6 Hz, 1H), 8.06 (s, 1H).

Step 54b: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Compound 0602-142)

The title compound, 0602-142 was prepared (450 mg, 73%) as a solid from0601-142 (500 mg, 2.5 mmol), bis(pinacolato)diboron (952 mg, 3.75 mmol),potassium acetate (735 mg, 7.5 mmol), and PdCl₂(dppf)₂ (61 mg, 0.075mmol) using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 248 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (s,12H), 7.34 (s, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.98(m, 1H), 8.04 (s, 1H), 8.19 (s, 1H).

Step 54c: Ethyl2-(((2-(3-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-142)

The title compound, 0603-142 was prepared (180 mg, 50%) as a yellowsolid from 0504-54 (305 mg, 0.68 mmol), 0602-142 (200 mg, 0.81 mmol),Pd(PPh₃)₂Cl₂ (21 mg, 0.03 mmol), and NaHCO₃ (171 mg, 2.04 mmol) intoluene (5 mL), ethanol (3 ml), and water (1.3 ml) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 534[M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.38 (t, J=7.6 Hz, 3H), 3.32 (s, 3H),3.87 (t, J=4.6 Hz, 4H), 4.03 (t, J=4.8 Hz, 4H), 4.37 (q, J=7.6 Hz, 2H),5.20 (s, 2H), 5.77 (br, 1H), 6.37 (br, 1H), 7.39 (s, 1H), 7.55 (t, J=7.8Hz, 1H), 7.96 (d, J=7.6 Hz, 4H), 8.59 (d, J=7.6 Hz, 1H), 8.84 (s, 1H),8.93 (s, 2H).

Step 54d:2-(((2-(3-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 142).

The title compound 142 was prepared (65 mg, 44%) as a yellow solid from0603-142 (150 mg, 0.28 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). LCMS: 521 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 3.25 (s,3H), 2.77-3.79 (m, 4H), 3.95-3.97 (m, 4H), 5.22 (s, 2H), 7.44 (s, 1H),7.50 (s, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.13 (s,1H), 8.52 (d, J=7.6 Hz, 1H), 8.76 (s, 2H), 8.96 (s, 1H), 9.03 (br, 1H),10.93 (br, 1H).

Example 55 Preparation ofN-hydroxy-2-(methyl((2-(3-(methylcarbamoyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 144)

Step 55a: 3-Bromo-N-methylbenzamide (Compound 0601-144)

A suspension of MeNH₂.HCl (1.85 g, 27 mmol) and Et₃N (4.6 g, 45 mmol) inanhydrous CH₂Cl₂ (50 mL) was cooled to 0° C. and treated withm-bromobenzoyl chloride (2 g, 9 mmol). The mixture was warmed to roomtemperature and stirred for 4 h. To the reaction mixture was added ethylacetate, washed with water, brine, and dried over Na₂SO₄, concentratedto give compound 0601-144 (1.9 g, 97%) as a white solid. LCMS: 214[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.78 (d, J=4.4 Hz, 3H), 7.43 (t,J=7.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 8.00 (s,1H), 8.57 (s, 1H).

Step 55b:N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Compound 0602-144)

The title compound, 0602-144 was prepared (480 mg, 82%) as a white solidfrom 0601-144 (500 mg, 2.3 mmol), bis(pinacolato)diboron (890 mg, 3.5mmol), potassium acetate (687 mg, 7 mmol), and PdCl₂(dppf)₂ (57.2 mg,0.07 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 262 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ1.21 (s, 12H), 2.77 (d, J=4.8 Hz, 3H), 7.47 (t, J=7.6 Hz, 1H), 7.79 (d,J=7.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 8.14 (s, 1H), 8.51 (m, 1H).

Step 55c: Ethyl2-(methyl((2-(3-(methylcarbamoyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-144)

The title compound, 0603-144 was prepared (250 mg, 68%) as a yellowsolid from 0504-54 (300 mg, 0.67 mmol), compound 0602-144 (349 mg, 1.34mmol), NaHCO₃ (168 mg, 2.0 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.03 mmol) intoluene (5 mL), ethanol (3 mL) and water (1.3 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 548[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H), 2.82 (d,J=4.8 Hz, 3H), 3.28 (s, 3H), 3.77 (m, 4H), 3.95 (m, 4H), 4.28 (q, J=6.8Hz, 2H), 5.24 (s, 2H), 7.52 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.91 (d,J=8.0 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.56 (m, 1H), 8.82 (s, 1H), 8.88(s,1H).

Step 55d:N-hydroxy-2-(methyl((2-(3-(methylcarbamoyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 144)

The title compound 144 was prepared (116 mg, 48%) as a yellow solid from0603-144 (250 mg, 0.45 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 215-217° C. LCMS: 535 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 2.81 (d, J=4.4 Hz, 3H), 3.25 (s, 3H), 3.78 (m, 4H), 3.95 (m,4H), 5.22 (s, 2H), 7.50 (s, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.91 (d, J=7.6Hz, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.56 (m, 1H), 8.76 (s, 2H), 8.82(s,1H).

Example 56 Preparation of2-(((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 150)

Step 56a: N-(4-bromophenyl)acetamide (Compound 0601-150)

To the solution of 4-bromoaniline (6.3 g, 63.7 mmol) in CH₂Cl₂ (50 mL)was added acetyl chloride (3.75 g, 47.7 mmol) and TEA (7.4 g, 73.4 mmol)at 0° C., stirred for 2 hours. The reaction mixture was washed withwater, brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the title compound 0601-150 (3.6 g, 46%) as abrown solid. LCMS: 214 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆). δ 2.05 (s,3H), 7.46 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 10.12 (s, 1H).

Step 56b:N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide(Compound 0602-150)

The title compound, 0602-150 was prepared (2.3 g, 94%) as a white solidfrom 0601-150 (2.0 g, 9.3 mmol), bis(pinacolato)diboron (4.4 g, 17.5mmol), potassium acetate (3.5 g, 14 mmol), and PdCl₂(dppf)₂ (76 mg,0.088 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 262 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.27 (d, J=6.8 Hz, 12H), 2.04 (s, 3H), 7.58 (s, 4H), 10.03 (s, 1H).

Step 56c: Ethyl2-(((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-150)

A mixture of compound 0504-54 (210 mg, 0.46 mmol), 0602-150 (159 mg,0.60 mmol), sodium hydrogen carbonate (118 mg, 1.4 mmol), andbis(triphenylphosphine)palladium(II) chloride (17 mg, 0.02 mmol) intoluene (4 mL), ethanol (2 mL) and water (1 mL) was flushed withnitrogen and heated under microwave irradiation at 120° C. for 2 h. Thereaction mixture was partitioned between ethyl acetate and water,organic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated in vacuum. The residue was washed withdichloromethane to obtain ethyl2-(((2-(4-acetamidophenyl)-4-morpholinothieno-[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(136 mg, 53%) as a white solid. LCMS: 548 [M+1]⁺, ¹H NMR (400 MHz,DMSO-d₆): δ 1.29 (t, J=7.2 Hz, 3H), 2.06 (s, 6H), 3.26 (s, 3H), 3.75 (m,4H), 3.91 (m, 4H), 4.28 (q, J=7.2 Hz, 2H), 5.22 (s, 2H), 7.45 (s,1H),7.67 (d, J=8.8 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 10.10(s, 1H).

To the solution of above ethyl ester (280 mg, 0.51 mmol) in THF (10 mL)was added aqueous HCl solution (6M, 15 mL) at 40° C., stirred for 2hours, the reaction mixture was neutralized with NaHCO₃ and extractedwith CH₂Cl₂, the organic layer was washed with water, brine, dried overNa₂SO₄, filtered, and concentrated, purified by column chromatography(methanol in dichloromethane, 2% v/v), to give title compound 0603-150(180 mg, 48%) as a white solid. LCMS: 506 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (t, J=7.6 Hz, 3H), 3.24 (s, 3H), 3.73 (m, 4H), 3.86 (m,4H), 4.27 (q, J=6.8 Hz, 2H), 5.20 (s, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.36(s, 1H), 8.07 (d, J=8.0 Hz, 2H), 8.86 (s, 1H).

Step 56d:2-(((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 150)

The title compound 150 was prepared (43 mg, 26%) as a yellow solid from0603-150 (170 mg, 0.3 mmol) and freshly prepared hydroxylamine methanolsolution (4 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 183-186° C. LCMS: 493 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆):δ 3.22 (s, 3H), 3.74 (m, 4H), 3.87 (m, 4H), 4.27 (q, J=6.8 Hz,2H), 5.20 (s, 2H), 5.50 (s, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.36 (s, 1H),8.07 (d, J=8.0 Hz, 2H), 8.86 (s, 2H).

Example 57 Preparation of2-(((2-(4-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 157)

Step 57a:2-(((2-(4-Acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 157)

The title compound 157 was prepared (104 mg, 61%) as a gray solid fromethyl2-(((2-(4-acetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(170 mg, 0.3 mmol) and freshly prepared hydroxylamine methanol solution(10 mL) using a procedure similar to that described for compound 3(Example 1). m.p. 228-230° C. LCMS: 535 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 2.07 (s, 3H), 3.24 (s, 3H), 3.77 (m, 4H), 3.91 (m, 4H), 5.19(s, 2H), 7.44 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 8.31 (d, J=8.8 Hz, 2H),8.75 (s, 2H), 9.06 (s, 1H), 10.12 (s, 1H), 11.13 (s, 1H).

Example 58 Preparation of2-(((2-(1H-indazol-4-yl)-4-(phenylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 164)

Step 58a: 2-Chloro-N-phenylthieno[3,2-d]pyrimidin-4-amine (Compound0701-164)

To a suspension of compound 0110 (4.00 g, 19.608 mmol) in CH₃CN (100 mL)was added Et₃N (4.00 g, 39.216 mmol) and aniline (2.00 g, 21.581 mmol)at room temperature. The mixture was stirred at 50° C. overnight,evaporated. The residue was purified by column chromatography on silicagel (ethyl acetate in petroleum ether, 20%-30% v/v) to obtained compound0701-164 (2.00 g, 39%) as a pale yellow solid. LCMS: 262 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆): δ 7.20 (t, J=7.6 Hz, 1H), 7.42 (m, 3H), 7.69 (d,J=7.6 Hz, 1H), 8.27 (d, J=5.2 Hz, 1H), 10.16 (s, 1H).

Step 58b: Tert-butyl2-chlorothieno[3,2-d]pyrimidin-4-yl(phenyl)carbamate (Compound 0702-164)

To a solution of compound 0701-164 (5.60 g, 21.456 mmol) and (Boc)₂O(5.60 g, 25.747 mmol) in THF (100 mL) was added DMAP (130 mg, 1.073mmol) at room temperature and stirred for 3 h. Solvent was removed andthe residue was purified by column chromatography (ethyl acetate inpetroleum ether, 15%-30% v/v) to obtained compound 0702-164 (6.20 g,80%) as a white solid. LCMS: 362 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.44 (s, 9H), 7.31 (d, J=7.6 Hz, 2H), 7.39 (m, 1H), 7.43 (m, 2H), 7.56(d, J=5.6 Hz, 1H), 8.48 (d, J=5.2 Hz, 1H).

Step 58c: Tert-butyl2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl(phenyl)carbamate (Compound0703-164)

Compound 0702-164 (2.90 g, 8.033 mmol) was suspended in THF (80 mL) andcooled to −50° C. To the mixture LDA solution (2M, 12 mL, 24.099 mmol)was added dropwise while temperature was kept below −30° C. and stirredfor 1 h followed by the addition of DMF (2 mL) at −50° C. The mixturewas stirred for additional 30 min. A saturated aqueous NH₄Cl (20 mL) wasadded dropwise at −50˜−60° C. Ethyl acetate (300 mL) was added to themixture, washed with saturated aqueous NH₄Cl (2×100 mL), water (2×100mL), brine (200 mL), dried over anhydrous Na₂SO₄, concentrated and theresidue was purified by column chromatography on silica gel (ethyl inpetroleum ether, 20%-50% v/v) to obtain compound 0703-164 (900 mg, 29%)as a yellowish solid. LCMS: 390 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.46 (s, 9H), 7.30 (d, J=6.8 Hz, 1H), 7.36 (m, 2H), 7.43 (m, 2H), 8.43(s, 1H), 10.21 (s, 1H).

Step 58d: Tert-butyl2-chloro-6-(hydroxymethyl)thieno[3,2-d]pyrimidin-4-yl(phenyl)carbamate(Compound 0704-164)

To a solution of 0703-164 (900 mg, 2.314 mmol) in MeOH/THF (10/5 mL) wasadded NaBH₄ (176 mg, 4.627 mmol) slowly at room temperature and stirredfor 30 min. After solvent removed, the residue was washed with water andfiltered to obtain 0704-164 (800 g, 88%) as a white solid. LCMS: 392[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.44 (s, 9H), 4.80 (d, J=5.6 Hz,2H), 6.02 (t, J=5.6 Hz, 1H), 7.28 (d, J=4.8 Hz, 2H), 7.37 (m, 2H), 7.45(m, 2H).

Step 58e:(4-(Tert-butoxycarbonyl(phenyl)amino)-2-chlorothieno[3,2-d]pyrimidin-6-yl)methylmethanesulfonate (Compound 0705-164)

To a solution of 0704-164 (500 mg, 1.279 mmol) and Et₃N (2 mL) in THF(20 mL) was added MsCl (175 mg, 1.534 mmol) at ice bath temperature. Themixture with white solid was stirred at room temperature for 30 min.After solvent removed, the residue was washed with water and filtered toobtain 0705-164 (600 mg, 83%) as a white solid. LCMS: 470 [M+1]⁺.

Step 58f:2-Chloro-6-((methylamino)methyl)-N-phenylthieno[3,2-d]pyrimidin-4-amine(Compound 0706-164)

Compound 0705-164 (600 mg, 1.279 mmol) was dissolved in a solution of32% MeNH₂ in MeOH (5 mL). This solution was stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure and the residuewas washed with water, filtered to obtained 0706-164 (300 mg, 77%) as awhite solid. LCMS: 305 [M+1]⁺.

Step 58g: Ethyl2-(((2-chloro-4-(phenylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0707-164)

To a solution of compound 0706-164 (260 mg, 0.855 mmol) and compound0305 (159 mg, 0.855 mmol) in CH₃CN (5 mL) was added Et₃N (0.5 mL) atroom temperature and stirred overnight. After concentrated, the residuewas washed with water, filtered to obtained compound 0707-164 (200 mg,52%) as a white solid. LCMS: 455 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.31 (t, J=4.2 Hz, 3H), 3.25 (s, 3H), 4.29 (m, 2H), 5.23 (s, 2H), 7.15(t, J=6.0 Hz. 1H), 7.37 (t, J=6.4 Hz, 2H), 7.42 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 8.88 (s, 2H), 9.98 (s, 1H).

Step 58h: Ethyl2-(((2-(1H-indazol-4-yl)-4-(phenylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0708-164)

The title compound, 0708-164 was prepared (210 mg, 89%) as a white solidfrom 0706-164 (200 mg, 0.440 mmol), compound 0107-3 (118 mg, 0.484mmol), NaHCO₃ (110 mg, 1.320 mmol), andbis(triphenylphosphine)-palladium(II) chloride (15 mg, 0.022 mmol) intoluene (5.6 mL), ethanol (3.5 mL), and water (1.4 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 537[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.33 (t, J=7.2 Hz, 3H), 3.31 (s,3H), 4.31 (m, 2H), 5.31 (s, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.41 (t, J=4.4Hz, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.65 (d, J=8.4 Hz, 1H),7.79 (d, J=7.6 Hz, 2H), 8.21 (d, J=7.2 Hz, 1H), 8.63 (s, 1H), 8.92 (s,2H), 9.66 (s, 1H), 13.16 (s, 1H).

Step 58i:2-(((2-(1H-indazol-4-yl)-4-(phenylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 164)

The title compound 164 was prepared (100 mg, 49%) as a pale white solidfrom 0708-164 (210 mg, 0.392 mmol) and freshly prepared hydroxylaminemethanol solution (8 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 232-235° C.; LCMS: 524 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆): δ 3.27 (s, 3H), 5.27 (s, 2H), 7.16 (t, J=7.2 Hz, 1H),7.41 (t, J=4.4 Hz, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.65 (d,J=8.4 Hz, 1H), 7.78 (d, J=7.6 Hz, 2H), 8.21 (d, J=7.2 Hz, 1H), 8.78 (s,2H), 8.81 (s, 1H), 9.07 (s, 1H), 9.64 (s, 1H), 11.15 (s, 1H), 13.14 (s,1H).

Example 59 Preparation of2-(((2-(1H-indazol-4-yl)-4-(pyridin-2-ylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 168)

Step 59a: 2-Chloro-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-amine(Compound 0701-168)

To a suspension of compound 0110 (5.00 g, 24.510 mmol) in THF (200 mL)was added t-BuOK (4.19 g, 36.765 mmol) and pyridin-2-amine (2.30 g,24.510 mmol) at room temperature. The mixture was stirred at 50° C.overnight, then the mixture was purified by column chromatography onsilica gel eluting with ethyl acetate in petroether (20% to 40%, v/v) toobtained compound 0701-168 (3.00 g, 47%) as a pale yellow solid. LCMS:263 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.18 (m, 1H), 7.43 (d, J=5.2Hz, 1H), 7.87 (m, 2H), 8.33 (d, J=5.6 Hz, 1H), 8.40 (d, J=4.8 Hz, 1H),10.94 (s, 1H).

Step 59b: Tert-butyl2-chlorothieno[3,2-d]pyrimidin-4-yl(pyridin-2-yl)carbamate (Compound0702-168)

The title compound 0702-168 was prepared (2.80 g, 100%) as a white solidfrom 0701-168 (2.40 g, 9.160 mmol), (Boc)₂O (3.00 g, 13.740 mmol), andDMAP (56 mg, 0.458 mmol) using a procedure similar to that described forcompound 0702-164 (Example 58). LCMS: 363 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 1.44 (s, 9H), 7.36 (m, 1H), 7.64 (m, 2H), 7.97 (t, J=7.6 Hz,1H), 8.34 (m, 1H), 8.54 (d, J=5.6 Hz, 1H).

Step 59c: Tert-butyl2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl(pyridin-2-yl)carbamate(Compound 0703-168)

The title compound 0703-168 was prepared (1.90 g, 48%) as a light yellowsolid from 0702-168 (3.69 g, 10.199 mmol), LDA solution (2M, 15.3 mL,30.597 mmol), and DMF (4 mL) using a procedure similar to that describedfor compound 0703-164 (Example 58). LCMS: 391 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 1.46 (s, 9H), 7.41 (m, 1H), 77.66 (d, J=8.0 Hz, 1H), 8.00(m, 1H), 8.40 (m, 1H), 8.49 (s, 1H), 10.12 (s, 1H).

Step 59d: Tert-butyl2-chloro-6-(hydroxymethyl)thieno[3,2-d]pyrimidin-4-yl(pyridin-2-yl)carbamate(Compound 0704-168)

The title compound 0704-168 was prepared (1.9 g, 100%) as a white solidfrom 0703-168 (1.9 g, 4.870 mmol) and NaBH₄ (277 mg, 7.31 mmol) using aprocedure similar to that described for compound 0704-164 (Example 58).LCMS: 393 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.44 (s, 9H), 4.84 (d,J=5.4 Hz, 2H), 6.05 (t, J=6.0 Hz, 1H), 7.34 (m, 1H), 7.43 (s, 1H), 7.65(d, J=8.0 Hz, 1H), 7.96 (t, J=7.6 Hz, 1H), 8.33 (m, 1H).

Step 59e:(4-(Tert-butoxycarbonyl(pyridin-2-yl)amino)-2-chlorothieno[3,2-d]pyrimidin-6-yl)methylmethanesulfonate (Compound 0705-168)

The title compound 0705-168 was prepared (2.10 g, 92%) as a white solidfrom 0704-168 (1.90 g, 4.847 mmol), Et₃N (2 mL), and MsCl (1.10 g, 9.694mmol) using a procedure similar to that described for compound 0705-164(Example 58). LCMS: 471 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.44 (s,9H), 3.31 (s, 3H), 5.68 (s, 2H), 7.37 (m, 1H), 7.65 (d, J=8.0 Hz, 1H),7.74 (s, 1H), 7.99 (t, J=7.6 Hz, 1H), 8.36 (m, 1H).

Step 59f:2-Chloro-6-((methylamino)methyl)-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-amine(Compound 0706-168)

The title compound 0706-168 was prepared (1.80 g, 100%) as a white solidfrom 0705-168 (2.00 g, 4.255 mmol) and 32% MeNH₂ in MeOH (5 mL) using aprocedure similar to that described for compound 0706-164 (Example 58).LCMS: 306 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 2.32 (s, 3H), 3.97 (s,2H), 7.15 (m, 1H), 7.26 (s, 1H), 7.83 (m, 2H), 8.38 (m, 1H), 9.71 (s,1H).

Step 59g: Ethyl2-(((2-chloro-4-(pyridin-2-ylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0707-168)

The title compound 0707-168 was prepared (410 mg, 69%) as a white solidfrom 0706-168 (400 mg, 1.311 mmol) and compound 0305 (244 mg, 1.311mmol) using a procedure similar to that described for compound 0707-164(Example 58). LCMS: 456 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.31 (t,J=7.2 Hz, 3H), 3.25 (s, 3H), 4.29 (m, 2H), 5.21 (s, 2H), 7.13 (m, 1H),7.40 (s, 1H), 7.84 (m, 2H), 8.30 (m, 1H), 8.88 (s, 2H), 10.84 (s, 1H).

Step 59h: Ethyl2-(((2-(1H-indazol-4-yl)-4-(pyridin-2-ylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0708-168)

The title compound, 0708-168 was prepared (200 mg, 85%) as a white solidfrom 0707-168 (200 mg, 0.440 mmol), compound 0107-3 (118 mg, 0.484mmol), NaHCO₃ (110 mg, 1.320 mmol), andbis(triphenylphosphine)-palladium(II) chloride (15 mg, 0.022 mmol) intoluene (8 mL), ethanol (5 mL), and water (2 mL) using a proceduresimilar to that described for compound 0603-107 (Example 30). LCMS: 538[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.33 (t, J=7.2 Hz, 3H), 3.29 (s,3H), 4.30 (m, 2H), 5.26 (s, 2H), 7.12 (m, 1H), 7.7.57 (s, 1H), 7.84 (m,1H), 8.23 (d, J=7.2 Hz, 1H), 8.33 (m, 1H), 8.89 (s, 2H), 10.39 (s, 1H),13.19 (s, 1H).

Step 59i:2-(((2-(1H-indazol-4-yl)-4-(pyridin-2-ylamino)thieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 168)

The title compound 168 was prepared (80 mg, 82%) as a pale white solidfrom 0708-168 (100 mg, 0.186 mmol) and freshly prepared hydroxylaminemethanol solution (8 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 200-203° C.; LCMS: 525 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆): δ 3.34 (s, 3H), 5.30 (s, 2H), 7.19 (t, J=6.0 Hz, 1H),7.55 (t, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.91 (t,J=8.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.41 (s,1H), 8.84 (s, 2H), 9.04 (s, 1H), 9.14 (s, 1H), 10.46 (s, 1H), 11.01 (s,1H), 13.25 (s, 1H).

Example 60 Preparation of5-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypentanamide(Compound 30)

Step 60a: Tert-butyl4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate(Compound 0801-30)

A mixture of compound 0110 (20 g, 98 mmol), tert-butyl1-piperazinecarboxylate (21.9 g, 118 mmol), and triethylamine (14.8 g,147 mmol) in methanol (400 mL) was stirred at room temperature for 4 h.The reaction mixture was filtered to give a solid as first batch ofcrude product. The mother liquid was concentrated and diluted with water(500 mL) and the solid was collected as second batch of crude product.The combined products were dried to give compound 0801-30 (22 g, 63%) asa yellow solid. LCMS: 355 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 1.43 (s,9H), 3.53 (m, 4H), 3.95 (m, 4H), 7.41 (d, J=5.6 Hz, 1H), 8.32 (d, J=5.6Hz, 1H).

Step 60b: Tert-butyl4-(2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate(Compound 0802-30)

Compound 0801-30 (10 g, 28.2 mmol) was suspended in THF (200 mL) andcooled to −70° C. followed by the addition of LDA solution (2M, 71 mL)dropwise and kept the reaction temperature below −65° C. The mixture wasthen stirred for 1 h. DMF (15 mL) was added dropwise to the mixturewhile the reaction temperature was kept below −65° C. The resultingmixture was stirred for 30 min. and quenched with saturated aqueousNH₄Cl (50 mL) at −50˜−60° C. The mixture was diluted with ethyl acetate(500 mL), washed with saturated aqueous NH₄HCO₃ (2×300 mL), water (2×500mL), brine (200 mL), dried over Na₂SO₄, concentrated and the residue waspurified by column chromatography on silica gel (methanol indichloromethane, 2% v/v) to give compound 0802-30 (4.9 g, 45%) as alight yellow solid. LCMS: 383 [M+1]⁻. ¹H NMR (400 MHz, DMSO-d₆): δ 1.43(s, 9H), 3.55 (m, 4H), 3.99 (m, 4H), 8.29 (s, 1H), 10.21 (s, 1H).

Step 60c: Tert-butyl4-(2-chloro-6-(hydroxymethyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate(Compound 0803-30)

To a suspension of compound 0802-30 (3.73 g, 9.764 mmol) in MeOH (20 mL)was added NaBH₄ (1.11 g, 29.293 mmol) slowly at 0° C. within 10 minutes.The formed clear solution was stirred for 10 min., evaporated. Theresidue was washed with water and filtered to obtain compound 0803-30(3.10 g, 83%) as a white solid. LCMS: 385 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆): δ 1.43 (s, 9H), 3.52 (br s, 4H), 3.92 (br s, 4H), 4.81 (d,J=4.8 Hz, 2H), 5.96 (t, J=5.2 Hz, 1H), 7.22 (s, 1H).

Step 60d: Tert-butyl4-(6-(bromomethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate(Compound 0804-30)

To a suspension of compound 0803-30 (3.10 g, 8.073 mmol) and PPh₃ (2.54g, 9.687 mmol) in dichloromethane (30 mL) was added NBS (1.72 g, 9.687mmol) at room temperature. The mixture was stirred at room temperaturefor 2 h and concentrated. The residue was purified by columnchromatography on silica gel (dichloromethane in petroleum ether, 10% to50% v/v) to obtain compound 0804-30 (2.60 g, 72%) as a white solid.LCMS: 447 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (s, 9H), 3.52 (br s,4H), 3.90 (br s, 4H), 5.10 (s, 2H), 7.49 (s, 1H).

Step 60e: Tert-butyl4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylate(Compound 0805-30)

A mixture of compound 0804-30 (3.5 g, crude product), compound 0103(1.14 g, 4.1 mmol), and K₂CO₃ (1.58 g, 11.4 mmol) in acetonitrile (35mL) and DMF (17 mL) was stirred at room temperature overnight. Thereaction mixture was diluted with water (200 mL) and extracted withdichloromethane (200 mL). The organic layer was washed with water (5×200mL), brine, dried over Na₂SO₄, concentrated to give crude product,compound 0805-30 (3.9 g with some Ph₃PO) as a yellow solid which wasused in next step reaction without further purification. LCMS: 531[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.42 (s, 9H), 2.59 (m, 4H), 2.90 (s,3H), 3.15 (m, 4H), 3.52 (m, 4H), 3.91 (m, 6H), 7.31 (s, 1H).

Step 60f:2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-(piperazin-1-yl)thieno[3,2-d]pyrimidine(Compound 0806-30)

To a solution of compound 0805-30 (5 g) in THF (50 mL) was addedconcentrated hydrochloric acid (10 mL) and stirred at room temperatureovernight. The reaction mixture was diluted with water (200 mL) andextracted with dichloromethane (100 mL). The orange layer was discardedafter washed with 0.1 M aqueous HCl (100 mL). The aqueous layer wasadjusted to pH 7 with solid NaHCO₃, extracted with dichloromethane (200mL). During extraction, small amount of methanol was added until thecolor of the solution turned to colorless from orange. The extracts wasdried over Na₂SO₄ and concentrated to give compound 0806-30 (1.9 g, 76%in two steps) as a yellow solid. LCMS: 431 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 2.57 (t, J=4.4 Hz, 4H), 2.83 (t, J=5.2 Hz, 4H), 2.90 (s, 3H),3.14 (t, J=4.4 Hz, 4H), 3.82 (t, J=4.4 Hz, 4H), 3.90 (s, 2H), 7.28 (s,1H).

Step 60g: Ethyl5-(4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)pentanoate(Compound 0807-30)

A mixture of compound 0806-30 (450 mg, 1.04 mmol), ethyl5-bromopentanoate (327 mg, 1.6 mmol), and triethylamine (211 mg, 2.1mmol) in DMF (8 mL) was stirred for 2 h at 80° C. The mixture was pouredinto water (100 mL) with stirring. The solid was collected by filtrationand purified by column chromatography on silica gel (methanol indichloromethane, 2% v/v) to give compound 0807-30 (500 mg, 86%) as alight yellow solid. LCMS: 560 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.18(t, J=7.2 Hz, 3H), 1.46 (m, 2H), 1.56 (m, 2H), 2.32 (m, 4H), 2.46 (m,4H), 2.57 (m, 4H), 2.90 (s, 3H), 3.14 (m, 4H), 3.88 (m, 6H), 4.05 (q,J=7.6 Hz, 2H), 7.29 (s, 1H).

Step 60h: Ethyl5-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)pentanoate(Compound 0808-30)

The title compound, 0808-30 was prepared (250 mg, 73%) as a yellow solidfrom 0807-30 (300 mg, 0.54 mmol), compound 0107-3 (157 mg, 0.64 mmol),NaHCO₃ (135 mg, 1.61 mmol), (Ph₃P)₂PdCl₂ (19 mg, 0.03 mmol) in toluene(5 mL), ethanol (3 mL), and water (1.3 mL) using a procedure similar tothat described for compound 0603-107 (Example 30). LCMS: 641 [M+1]⁻. ¹HNMR (400 MHz, DMSO-d₆) δ 1.19 (t, J=7.2 Hz, 3H), 1.51 (m, 2H), 1.56 (m,2H), 2.33 (m, 4H), 2.58 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.94 (m,2H), 4.06 (m, 6H), 7.47 (m, 2H), 7.66 (d, J=8.4 Hz, 1H). 8.21 (d, J=7.2Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).

Step 60i:5-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypentanamide(Compound 30)

The title compound 30 was prepared (95 mg, 39%) as a white solid from0808-30 (250 mg, 0.39 mmol) and freshly prepared hydroxylamine methanolsolution (6 mL) using a procedure similar to that described for compound3 (Example 1). mp 142-145° C. LCMS: 628 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.53 (m, 4H), 1.99 (t, J=6.8 Hz, 2H) 2.35 (t, J=6.8 Hz, 2H),2.59 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.94 (s, 2H), 4.02 (m, 4H),7.47 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.22 (d, J=6.8 Hz,1H), 8.88 (s, 1H), 10.36 (s, 1H), 13.20 (s, 1H).

Example 61 Preparation of6-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxyhexanamide(Compound 31)

Step 61a: Ethyl6-(4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)hexanoate(Compound 0807-31)

The title compound, 0807-31 was prepared (290 mg, 44%) as a yellow solidfrom 0806 (400 mg, 0.928 mmol), ethyl 6-bromohexanoate (310 mg, 1.39mmol), and triethylamine (187 mg, 1.86 mmol) using a procedure similarto that described for compound 0807-30 (Example 60). LCMS: 573 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.18 (t, J=7.2 Hz, 3H), 1.29 (m, 2H), 1.45(m, 2H), 1.54 (m, 2H), 2.29 (m, 4H), 2.50 (m, 4H), 2.57 (m, 4H), 2.90(s, 3H), 3.14 (m, 4H), 3.88 (m, 6H), 4.05 (q, J=7.2 Hz, 2H), 7.29 (s,1H).

Step 61b: Ethyl6-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)hexanoate(Compound 0808-31)

The title compound, 0808-31 was prepared (300 mg, 91%) as a yellow solidfrom 0807-31 (290 mg, 0.506 mmol), compound 0107-3 (185 mg, 0.607 mmol),NaHCO₃ (128 mg, 1.52 mmol), (Ph₃P)₂PdCl₂ (18 mg, 0.025 mmol) in toluene(5 mL), ethanol (3 mL) and water (1.3 mL) using a procedure similar tothat described for compound 0603-107 (Example 30). LCMS: 655 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.17 (t, J=6.8 Hz, 3H), 1.20 (m, 2H), 1.52 (m,4H), 2.32 (m, 4H), 2.58 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.95 (m,2H), 4.01 (m, 4H), 4.05 (q, J=6.8 Hz, 2H), 7.48 (m, 2H), 7.66 (d, J=8.0Hz, 1H). 8.21 (d, J=6.8 Hz, 1H), 8.88 (s, 1H), 13.20 (s, 1H).

Step 61c:6-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxyhexanamide(Compound 31)

The title compound 31 was prepared (41 mg, 14%) as a white solid from0808-31 (300 mg, 0.46 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 140-145° C. LCMS: 642 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ1.28 (m, 2H), 1.51 (m, 4H), 1.96 (t, J=7.2 Hz, 2H) 2.33 (t,J=7.2 Hz, 2H), 2.60 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.94 (s, 2H),4.01 (m, 4H), 7.47 (m, 2H), 7.66 (d, J=8.0 Hz, 1H). 8.21 (d, J=7.2 Hz,1H), 8.68 (s, 1H), 8.88 (s, 1H), 10.35 (s, 1H), 13.20 (s, 1H).

Example 62 Preparation of7-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxyheptanamide(compound 32)

Step 62a: Ethyl7-(4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)heptanoate(Compound 0807-32)

The title compound, 0807-32 was prepared (550 mg, 81%) as a yellow solidfrom 0806 (500 mg, 1.16 mmol), ethyl 7-bromoheptanoate (412 mg, 1.74mmol), triethylamine (235 mg, 2.3 mmol) using a procedure similar tothat described for compound 0807-30 (Example 60). LCMS: 587 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.18 (t, J=7.2 Hz, 3H), 1.28 (m, 4H), 1.45 (m,2H), 1.52 (m, 2H), 2.29 (m, 4H), 2.46 (m, 4H), 2.57 (m, 4H), 2.90 (s,3H), 3.14 (m, 4H), 3.89 (m, 6H), 4.05 (q, J=7.2 Hz, 2H), 7.29 (s, 1H).

Step 62b: Ethyl7-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)heptanoate(Compound 0808-32)

The title compound, 0808-32 was prepared (220 mg, 63%) as a yellow solidfrom 0807-32 (300 mg, 0.51 mmol), compound 0107-3 (150 mg, 0.61 mmol),NaHCO₃ (129 mg, 1.53 mmol), (Ph₃P)₂PdCl₂ (18 mg, 0.026 mmol) in toluene(5 mL), ethanol (3 mL), and water (1.3 mL) using a procedure similar tothat described for compound 0603-107 (Example 30). LCMS: 669 [M+1]⁻. ¹HNMR (400 MHz, DMSO-d₆) δ 1.18 (t, J=7.2 Hz, 3H),1.30 (m, 4H), 1.52 (m,2H), 1.55 (m, 2H), 2.30 (m, 4H), 2.57 (m, 8H), 2.91 (s, 3H), 3.17 (m,4H), 3.94 (m, 2H), 4.06 (m, 6H), 7.47 (m, 2H), 7.66 (d, J=8.4 Hz, 1H).8.21 (d, J=7.2 Hz, 1H), 8.88 (s, 1H), 13.19 (s, 1H).

Step 62c:7-(4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)-N-hydroxyheptanamide(Compound 32)

The title compound 32 was prepared (80 mg, 37%) as a white solid from0808-32 (220 mg, 0.33 mmol) and freshly prepared hydroxylamine methanolsolution (6 mL) using a procedure similar to that described for compound3 (Example 1). mp 131-134° C. LCMS: 656 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.29 (m, 4H), 1.49 (m, 4H), 1.95 (t, J=6.8 Hz, 2H), 2.35 (t,J=6.4 Hz, 2H), 2.60 (m, 8H), 2.91 (s, 3H), 3.17 (m, 4H), 3.95 (m, 6H),7.47 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.22 (d, J=7.2 Hz,1H), 8.88 (s, 1H), 10.35 (s, 1H), 13.20 (s, 1H).

Example 63 Preparation of2-(((2-(6-acetamidopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 112)

Step 63a: N-(5-bromopyridin-2-yl)acetamide (Compound 0601-112)

To a solution of 2-amino-5-bromopyridine (0.50 g, 2.9 mmol) in THF (10mL) was added pyridine (343 mg, 4.3 mmol) and acetic anhydride (295 mg,2.9 mmol) at room temperature and stirred overnight. To the mixturewater (30 mL) was added, extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with saturated aqueous NaHCO₃ andbrine, dried over Na₂SO₄, concentrated to give the title compound (0.58g, 92%) as a white solid LCMS: 215 [M+2]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ2.09 (s, 3H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.41(d, J=1.2 Hz, 1H), 10.64 (s, 1H).

Step 63b:N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(compound 0602-112)

The title compound 0602-112 was prepared (400 mg, 57%) as a yellow solidfrom 0601-112 (0.57 g, 2.7 mmol), bis(pinacolato)diboron (1.00 g, 4.0mmol), potassium acetate (0.78 g, 8.0 mmol), and PdCl₂(dppf)₂ (217 mg,0.3 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 263 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 1.30(s, 12H), 2.10 (s, 3H), 7.96 (dd, J=8.4, 1.6 Hz, 1H), 8.09 (d, J=8.4 Hz,1H), 8.51 (d, J=0.4 Hz, 1H), 10.65 (s, 1H).

Step 63c: Ethyl2-(((2-(6-acetamidopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-112)

The title compound 0603-112 was prepared (120 mg, 73%) as a off-whitesolid from 0504-54 (135 mg, 0.30 mmol), 0602-112 (157 mg, 0.60 mmol),NaHCO₃ (76 mg, 0.90 mmol), (Ph₃P)₂PdCl₂ (11 mg, 0.015 mmol) in toluene(2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a procedure similarto that described for compound 0603-107 (Example 34). LCMS: 549 [M+1]⁺;¹HNMR (400 MHz, CDCl₃) δ 1.38 (t, J=7.2 Hz, 3H), 2.25 (s, 3H), 3.31 (s,3H), 3.87 (t, J=4.4 Hz, 4H), 4.01 (t, J=4.4 Hz, 4H), 4.36 (q, J=7.2 Hz,2H), 5.20 (s, 2H), 7.38 (s, 1H), 8.28 (m, 2H), 8.70 (dd, J=8.8, 2.0 Hz,1H), 9.28 (d, J=2.0 Hz, 1H).

Step 63d:2-(((2-(6-Acetamidopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 112)

The title compound 112 was prepared (20 mg, 19%) as a yellow solid from0603-112 (108 mg, 0.20 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 197-201° C. LCMS: 536 [M+1]⁺; ¹HNMR (400MHz, DMSO-d₆) δ 2.13 (s, 3H), 3.24 (s, 3H), 3.76 (t, J=4.4 Hz, 4H), 3.93(t, J=4.4 Hz, 4H), 5.21 (s, 2H), 7.46 (s, 1H), 8.18 (d, J=8.8 Hz, 1H),8.64 (d, J=1.2 Hz, 1H), 8.75 (s, 2H), 9.24 (d, J=2.0 Hz, 1H), 10.72 (s,1H).

Example 64 Preparation of2-(((2-(6-(dimethylamino)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 114)

Step 64a: 5-Bromo-N,N-dimethylpyridin-2-amine (Compound 0601-114)

To a solution of 5-bromopyridin-2-amine (1.0 g, 5.8 mmol) in THF (25 mL)was added NaH (0.92 g, 23.1 mmol) at 0° C. and stirred for 10 min.followed by the addition of CH₃I (1 mL, 16 mmol) and stirred for 1 h.Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated and purified by column chromatography on silica gel (ethylacetate in petroleum ether, 10% v/v) to give the title compound (1.1 g,94%) as a white solid LCMS: 203 [M+2]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 2.99(s, 6H), 6.61 (d, J=9.6 Hz, 1H), 7.62 (dd, J=9.2, 2.8 Hz, 1H), 8.12 (d,J=2.4 Hz, 1H).

Step 64b:N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(Compound 0602-114)

The title compound 0602-114 was prepared (0.81 g, 67%) as a yellow solidfrom 0601-114 (1.0 g, 5.0 mmol), bis(pinacolato)diboron (1.90 g, 7.5mmol), potassium acetate (1.46 g, 14.9 mmol), and PdCl₂(dppf)₂ (1.90 g,7.5 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 167 [M−81]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ1.27 (s, 12H), 3.05 (s, 6H), 6.58 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.4,1.6 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H).

Step 64c: Ethyl2-(((2-(6-(dimethylamino)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-114)

The title compound 0603-114 was prepared (98 mg, 61%) as a off-whitesolid from 0504-54 (135 mg, 0.30 mmol), 0602-114 (149 mg, 0.60 mmol),NaHCO₃ (76 mg, 0.90 mmol), (Ph₃P)₂PdCl₂ (11 mg, 0.015 mmol) in toluene(2.5 mL), ethanol (1.6 mL) and water (0.7 mL) using a procedure similarto that described for compound 0603-107 (Example 34). LCMS: 535 [M+1]⁺;¹HNMR (400 MHz, CDCl₃) δ 1.38 (t, J=7.2 Hz, 3H), 3.18 (s, 6H), 3.30 (s,3H), 3.84 (t, J=4.8 Hz, 4H), 3.99 (t, J=4.8 Hz, 4H), 4.36 (q, J=7.2 Hz,2H), 5.18 (s, 2H), 6.58 (d, J=9.2, 1H), 7.37 (s, 1H), 8.49 (d, J=7.6 Hz,1H), 8.93 (s, 2H), 9.25 (d, J=2.0 Hz, 1H).

Step 64d:2-(((2-(6-(Dimethylamino)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 114)

The title compound 114 was prepared (75 mg, 82%) as a yellow solid from0603-114 (93 mg, 0.17 mmol) and freshly prepared hydroxylamine methanolsolution (5 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 190-195° C. LCMS: 522 [M+1]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 3.10 (s, 6H), 3.23 (s, 3H), 3.74 (s, 4H), 3.89 (s, 4H), 5.19(s, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.40 (s, 1H), 8.37 (d, J=7.2 Hz, 1H),8.75 (s, 2H), 9.09 (s, 2H), 11.14 (d, J=1.2 Hz, 1H).

Example 65 Preparation of2-(((2-(2-(aminomethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 124)

Step 65a: Tert-butyl(5-bromopyrimidin-2-yl)methylcarbamate (Compound0601-124)

A mixture of 5-bromo-2-methylpyrimidine (100 mg, 0.58 mmol), NBS (103mg, 0.58 mmol), dibenzoyl peroxide (10 mg, 0.04 mmol) intetrachloromethane (10 mL) was refluxed for 36 h. The solvent wasremoved in vacuo and the residue was purified by column chromatographyon silica gel (ethyl acetate in petroleum ether, 1% v/v) to give5-Bromo-2-(bromomethyl)pyrimidine (70 mg, 48%) as a white solid. ¹HNMR(400 MHz, CDCl₃) δ 4.49 (s, 2H), 8.72 (s, 2H).

A solution of 5-Bromo-2-(bromomethyl)pyrimidine (350 mg, 1.4 mmol) inmethanol (5 mL) was added to aqueous ammonia solution (25-28%, 10 mL)and stirred for 2 hours at room temperature. The solvent was removedfollowed by addition of ethanol (20 mL). The solvent was evaporated andto the residue was added dichloromethane (10 mL), triethylamine (379 mg,3.72 mmol), Boc₂O (603 mg, 2.79 mmol), DMAP (22 mg, 0.19 nmmol). Theresulting mixture was stirred for 2 hours at room temperature. Thesolvent was removed and purified by column chromatography on silica gelto give 0601-124 (380 mg, 82%) as a white solid. LCMS: 232 [M−56]⁺;¹HNMR (400 MHz, DMSO-d₆) δ 1.38 (s, 9H), 4.28 (d, J=5.6 Hz, 2H), 7.30(t, J=6.4 Hz, 1H), 8.95 (s, 2H).

Step 65b:Tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)methylcarbamate(Compound 0602-124)

The title compound 0602-124 was prepared (410 mg, 93%) as a yellow oilfrom 0601-124 (380 mg, 1.3 mmol), bis(pinacolato)diboron (0.50 g, 2.0mmol), potassium acetate (388 mg, 4.0 mmol), and PdCl₂(dppf)₂ (108 mg,0.1 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 198 [M−137]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ1.32 (s, 12H), 1.39 (s, 9H), 4.33 (d, J=6.0 Hz, 2H), 7.30 (t, J=6.0 Hz,1H), 8.87 (s, 1H).

Step 65c: Ethyl2-(((2-(2-(aminomethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-124)

The compound ethyl2-(((2-(2-((tert-butoxycarbonylamino)methyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylatewas prepared (248 mg, 66%) as a white solid from 0504-54 (270 mg, 0.6mmol), 0602-124 (395 mg, 1.2 mmol), NaHCO₃ (152 mg, 1.8 mmol),(Ph₃P)₂PdCl₂ (21 mg, 0.03 mmol) in toluene (5 mL), ethanol (3.2 mL) andwater (1.4 mL) using a procedure similar to that described for compound0603-107 (Example 34). LCMS: 622 [M+1]⁺; ¹HNMR (400 MHz, CDCl₃) δ 1.39(t, J=7.2 Hz, 3H), 1.49 (s, 9H), 3.33 (s, 3H), 3.87 (t, J=4.4 Hz, 4H),4.01 (t, J=4.4 Hz, 4H), 4.37 (q, J=7.2 Hz, 2H), 4.68 (d, J=4.4 Hz, 2H),5.21 (s, 2H), 5.79 (s, 1H), 7.40 (s, 1H), 8.94 (s, 2H), 9.62 (s, 2H).

To a solution of above compound (247 mg, 0.4 mmol) in CH₂Cl₂ (3 mL) wasadded TFA (1.5 mL) and stirred at room temperature for 4 h. Water (50mL) was added and extracted with CH₂Cl₂ (200 mL). The organic layer waswashed with saturated aqueous NaHCO₃, brine, dried and concentrated. Theresidue was recrystallized from ethyl acetate and petroleum ether (50%v/v) to give 0603-124 (300 mg, 100%) as an off-white solid. LCMS: 522[M+1]⁺; ¹HNMR (400 MHz, CDCl₃) δ 1.28 (t, J=6.8 Hz, 3H), 3.26 (s, 3H),3.75 (d, J=4.4 Hz, 4H), 3.94 (d, J=4.4 Hz, 6H), 4.26 (q, J=7.2 Hz, 2H),5.23 (s, 2H), 7.51 (s, 1H), 8.86 (s, 2H), 9.54 (s, 2H).

Step 65d:2-(((2-(2-(Aminomethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 124)

The title compound 124 was prepared (110 mg, 54%) as a yellow solid from0603-124 (300 mg, 0.6 mmol) and freshly prepared hydroxylamine methanolsolution (16 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.:>300° C. LCMS: 509 [M+1]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 3.17 (s, 6H), 3.17 (s, 3H), 3.74 (s, 4H), 3.92 (s, 4H), 3.95(s, 2H), 5.19 (s, 2H), 7.48 (s, 1H), 8.73 (s, 2H), 9.53 (s, 2H).

Example 66 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-phenylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 129)

Step 66a: Ethyl2-(methyl((4-morpholino-2-phenylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-129)

The title compound 0603-129 was prepared (250 mg, 64%) as a yellow solidfrom 0504-54 (358 mg, 0.80 mmol), phenylboronic acid (195 mg, 1.60mmol), Cs₂CO₃ (520 mg, 1.60 mmol) and Pd(dppf)₂Cl₂ (65 mg, 0.08 mmol) in1,4-dioxane (6 mL) and water (0.2 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 491 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 3.28 (s, 3H), 3.76 (t,J=4.8 Hz, 4H), 3.94 (t, J=4.8 Hz, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.24 (s,2H), 7.47-7.50 (m, 4H), 8.38-8.41 (m, 2H), 8.89 (s, 2H).

Step 66b:N-hydroxy-2-(methyl((4-morpholino-2-phenylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 129)

The title compound 129 was prepared (140 mg, 72%) as a yellow solid from0603-129 (200 mg, 0.41 mmol) and freshly prepared hydroxylamine methanolsolution (15 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 199-200° C. LCMS: 478 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.76 (s, 4H), 3.93 (s, 4H), 5.20 (s, 2H),7.47 (m, 4H), 8.39 (m, 2H), 8.75 (s, 2H).

Example 67 Preparation ofN-hydroxy-2-(((2-(4-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 131)

Step 67a: Ethyl2-(((2-(4-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-131)

The title compound 0603-131 was prepared (230 mg, 66%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 4-methoxylphenylboronic acid (204 mg,1.34 mmol), Pd(PPh₃)₂Cl₂ (24 mg, 0.03 mmol), NaHCO₃ (202 mg, 2.01 mmol)in toluene (5 mL), ethanol (3 mL), and water (1.3 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 521[M+1]⁺. ¹H NMR (400 M Hz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 3.27 (s,1H), 3.75 (t, J=4.4 Hz, 4H), 3.82 (s, 3H), 3.91 (t, J=4.6 Hz, 4H), 4.29(dd, J=7.2, 7.2 Hz, 2H), 5.22 (s, 2H), 7.02 (d, J=9.2 Hz, 2H), 7.45 (s,1H), 8.33 (d, J=8.8 Hz, 2H), 8.88 (s, 2H).

Step 67b:N-hydroxy-2-(((2-(4-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 131)

The title compound 131 was prepared (60 mg, 23%) as a yellow solid from0603-131 (230 mg, 0.44 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p. 247° C. (Decomposed); LCMS: 509 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.24 (s, 3H), 3.75-3.77 (m, 4H), 3.82 (s, 3H), 3.90-3.92(m, 4H), 5.20 (s, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.43 (s, 1H), 8.34 (d,J=8.4 Hz, 2H), 8.75 (s, 2H), 9.08 (br, 1H), 11.12 (br, 1H).

Example 68 Preparation ofN-hydroxy-2-(((2-(4-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 133)

Step 68a: Ethyl2-(((2-(4-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-133)

The title compound 0603-133 was prepared (170 mg, 50%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 4-hydroxylphenylboronic acid (111 mg,0.802 mmol), NaHCO₃ (168 mg, 2.00 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.0334mmol) in ethanol (2.3 mL), toluene (4 mL), and water (1 mL) using aprocedure similar to that described for compound 0603-107 (Example 34).LCMS: 507 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H),3.27 (s, 3H), 3.75 (m, 4H), 3.90 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.22(s, 2H), 6.84 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 8.23 (d, J=8.4 Hz, 2H),8.88 (s, 2H), 9.81 (s, 1H).

Step 68b:N-hydroxy-2-(((2-(4-hydroxyphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 133)

The title compound 133 was prepared (69 mg, 42%) as a white solid from0603-133 (170 mg, 0.336 mmol) and freshly prepared hydroxylaminemethanol solution (10 mL) using a procedure similar to that describedfor compound 3 (Example 1). mp. 185-195° C. LCMS: 494 [M+1]⁻. ¹H NMR(400 MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.75 (m, 4H), 3.90 (m, 4H), 5.19 (s,2H), 6.84 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.75(s, 2H), 9.90 (s, 2H).

Example 69 Preparation of2-(((2-(4-(acetamidomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 136)

Step 69a:2-(((2-(4-(Acetamidomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 136)

The title compound 136 was prepared (75 mg, 31%) as a white solid fromethyl2-(((2-(4-(acetamidomethyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(250 mg, 0.45 mmol, example 48) and freshly prepared hydroxylaminemethanol solution (20 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 178-180° C. LCMS: 549 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 1.89 (s, 3H), 3.23 (s, 3H), 3.76 (m, 4H), 3.91 (m,4H), 4.31 (d, J=5.6 Hz, 2H), 5.20 (s, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.45(s, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.41 (t, J=5.6 Hz, 1H), 8.75 (s, 2H).

Example 70 Preparation of2-(((2-(4-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 143)

Step 70a: 4-Bromobenzamide (Compound 0601-143)

To a solution of 4-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) wasadded 30% H₂O₂ (5 g, 13 mmol) and K₂CO₃ at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto water and filtered. The collected solid was washed with water anddried to get the compound 0601-143 (2.1 g, 96%) as a white solid. LCMS:200 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (s, 1H), 7.67 (d, J=8.4 Hz,2H), 7.81 (d, J=8.4 Hz, 2H), 8.06 (s, 1H).

Step 70b: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Compound 0602-143)

The title compound 0602-143 was prepared (570 mg, 92%) from 0601-143(500 mg, 2.5 mmol), bis(pinacolato)diboron (952 mg, 3.75 mmol),potassium acetate (735 mg, 7.5 mmol), and PdCl₂(dppf)₂ (61 mg, 0.075mmol) using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 248 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (s,12H), 7.43 (s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.87 (d, J=7.6 Hz, 2H), 8.03(s, 1H).

Step 70c: Ethyl2-(((2-(4-carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-143)

The title compound 0603-143 was prepared (300 mg, 84%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 0602-143 (330 mg, 1.34 mmol), NaHCO₃(168 mg, 2.0 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.03 mmol) in toluene (5 mL),ethanol (3 mL) and water (1.3 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 534 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H), 3.28 (s, 3H), 3.77 (m, 4H),3.93 (m, 4H), 4.28 (q, J=7.2 Hz, 2H), 5.24 (s, 2H), 7.45 (s, 1H), 7.51(s, 1H), 7.97 (d, J=8.4 Hz, 2H),8.07 (s, 1H), 8.43 (d, J=8.4 Hz, 2H),8.88 (s, 2H).

Step 70d:2-(((2-(4-Carbamoylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 143)

The title compound 143 was prepared (183 mg, 63%) as a yellow solid from0603-143 (300 mg, 0.47 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). mp 200-202° C. LCMS: 521 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 3.25 (s, 3H), 3.77 (m, 4H), 3.94 (m, 4H), 5.21 (s, 2H), 7.46(s, 1H), 7.49 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 8.08 (s, 1H), 8.44 (d,J=8.4 Hz, 2H), 8.76 (s,1H).

Example 71 Preparation of2-(((2-(4-cyanophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 146)

Step 71a: Ethyl2-(((2-(4-cyanophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-146)

The title compound 0603-146 was prepared (400 mg, 70%) as a off-whitesolid from 0504-54 (500 mg, 1.1 mmol), 4-cyanophenylboronic acid (245mg, 1.67 mmol), NaHCO₃ (280 mg, 3.34 mmol), (Ph₃P)₂PdCl₂ (39 mg, 0.05mmol) in toluene (5 mL), ethanol (3 mL) and water (1.3 mL) using aprocedure similar to that described for compound 0603-107 (Example 34).LCMS: 516 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.39 (t, J=7.6 Hz, 3H), 3.32(s, 3H), 3.87 (m, 4H), 4.02 (m, 4H), 4.36 (q, J=7.2 Hz, 2H), 5.21 (s,2H), 7.39 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 8.53 (d, J=8.8 Hz, 2H), 8.93(s, 2H).

Step 71b:2-(((2-(4-Cyanophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 146)

The title compound 146 was prepared (40 mg, 10%) as an off-white solidfrom 0603-146 (400 mg, 0.77 mmol) and freshly prepared hydroxylaminemethanol solution (12 mL) using a procedure similar to that describedfor compound 3 (Example 1). mp 214-216° C. LCMS: 503 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.24 (s, 3H), 3.77 (m, 4H), 3.95 (m, 4H), 5.22 (s, 2H),7.51 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 8.54 (d, J=8.2 Hz, 2H), 8.75(s,2H), 9.13 (s, 1H), 11.11 (s, 1H).

Example 72 Preparation of2-(((2-(4-chlorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 147)

Step 72a: Ethyl2-(((2-(4-chlorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-147)

The title compound 0603-147 was prepared (250 mg, 73%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 4-chlorophenylboronic acid (209 mg,1.34 mmol), Pd(PPh₃)₂Cl₂ (24 mg, 0.03 mmol), NaHCO₃ (202 mg, 2.01 mmol)in toluene (5 mL), ethanol (3 mL), and water (1.3 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 525[M+1]⁺. ¹H NMR (400 M Hz, DMSO-d₆) δ 1.30 (t, J=7.0 Hz, 3H), 3.27 (s,3H), 3.76 (t, J=4.8 Hz, 4H), 3.92 (t, J=4.8 Hz, 4H), 4.29 (dd, J=6.8,7.2 Hz, 2H), 5.24 (s, 2H), 7.50 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 8.40(d, J=8.4 Hz, 2H), 8.88 (s, 2H).

Step 72b:2-(((2-(4-chlorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 147)

The title compound 147 was prepared (69 mg, 29%) as a white solid from0603-147 (250 mg, 0.48 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). mp. 153-153° C.; LCMS: 512 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 3.24 (s, 3H), 3.75-3.77 (m, 4H), 3.91-3.93 (m, 4H), 5.21 (s,2H), 7.47 (s, 1H), 7.54 (d, J=7.6 Hz, 2H), 8.39 (d, J=8.0 Hz, 2H), 8.76(s, 2H), 9.07 (br, 1H), 11.14 (br, 1H).

Example 73 Preparation ofN-hydroxy-2-(((2-(4-isopropylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 148)

Step 73a: Ethyl2-(((2-(4-isopropylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-148)

The title compound 0603-148 was prepared (250 mg, 73%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 4-isopropylphenylboronic acid (220 mg,1.34 mmol), Pd(PPh₃)₂Cl₂ (24 mg, 0.03 mmol), NaHCO₃ (202 mg, 2.01 mmol)in toluene (5 mL), ethanol (3mL), and water (1.3 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 533[M+1]⁺. ¹H NMR (400 M Hz, DMSO-d₆) δ 1.24 (d, J=7.2 Hz, 6H), 1.30 (t,J=7.2 Hz, 3H), 2.90-2.98 (m, 1H), 3.27 (s, 3H), 3.76 (t, J=4.6 Hz, 4H),3.92 (t, J=4.4 Hz, 4H), 4.29 (dd, J=7.2, 7.2 Hz, 2H), 5.23 (s, 2H), 7.34(d, J=8.0 Hz, 2H), 7.48 (s, 1H), 8.30 (d, J=8.4 Hz, 2H), 8.88 (s, 2H).

Step 73b:N-hydroxy-2-(((2-(4-isopropylphenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 148)

The title compound 148 was prepared (58 mg, 27%) as a white solid from0603-148 (250 mg, 0.47 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). mp. 155° C. (decomposed); LCMS: 520 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 1.24 (d, J=6.4 Hz, 6H), 2.92-2.98 (m, 1H), 3.24 (s, 3H),3.75-3.77 (m, 4H), 3.91-3.93 (m, 4H), 5.20 (s, 2H), 7.34 (d, J=8.0 Hz,2H), 7.46 (s, 1H), 8.30 (d, J=8.0 Hz, 2H), 8.76 (s, 2H), 9.08 (br, 1H),11.10 (br, 1H).

Example 74 Preparation ofN-hydroxy-2-(methyl((2-(4-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 149)

Step 74a: Ethyl2-(methyl((2-(4-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-149)

The title compound 0603-149 was prepared (250 mg, 77%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 4-(methanesulfonyl)phenylboronic acid(268 mg, 1.34 mmol), Pd(PPh₃)₂Cl₂ (24 mg, 0.03 mmol), NaHCO₃ (202 mg,2.01 mmol) in toluene (5 mL), ethanol (3 mL), and water (1.3 mL) using aprocedure similar to that described for compound 0603-107 (Example 34).LCMS: 569 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H),3.27 (s, 3H), 3.28 (s, 3H), 3.76-3.78 (m, 4H), 3.95-3.97 (m, 4H), 4.29(q, J=7.2 Hz, 2H), 5.25 (s, 2H), 7.54 (s, 1H), 8.03 (d, J=8.4 Hz, 2H),8.61 (d, J=8.8 Hz, 2H), 8.88 (s, 2H).

Step 74b:N-hydroxy-2-(methyl((2-(4-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 149)

The title compound 149 was prepared (160 mg, 65%) as a white solid from0603-149 (250 mg, 0.44 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). mp. 206-208° C.; LCMS: 556 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 3.24 (s, 3H), 3.26 (s, 3H), 3.77 (t, J=4.4 Hz, 4H), 3.96 (t,J=4.4 Hz, 4H), 5.22 (s, 2H), 7.52 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 8.61(d, J=8.8 Hz, 2H), 8.75 (s, 2H), 9.06 (br, 1H), 11.13 (br, 1H).

Example 75 Preparation of2-(((2-(4-fluorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 200)

Step 75a: Ethyl2-(((2-(4-fluorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-200)

The title compound 0603-200 was prepared (300 mg, 76%) as a white solidfrom 0504-54 (350 mg, 0.78 mmol), 4-fluorophenylboronic acid (164 mg,1.17 mmol), Pd(PPh₃)₂Cl₂ (27 mg, 0.039 mmol), NaHCO₃ (196 mg, 2.34 mmol)in toluene (8 mL), ethanol (5 mL), and water (2 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 509[M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.31 (t, J=7.2 Hz, 3H), 3.24 (s, 3H)3.80 (t, J=4.8 Hz, 4H), 3.94 (t, J=4.6 Hz, 4H), 4.30 (q, J=7.1 Hz, 2H),5.13 (s, 2H), 7.04-7.08 (m, 2H), 7.30 (s, 1H), 8.34-8.37 (m, 2H), 8.86(s, 2H).

Step 75b:2-(((2-(4-fluorophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 200)

The title compound 200 was prepared (240 mg, 82%) as an off-white solidfrom 0603-200 (300 mg, 0.59 mmol) and freshly prepared hydroxylaminemethanol solution (16 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 168-170° C. LCMS: 496 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆):δ 3.23 (s, 3H), 3.76 (t, J=4.6 Hz, 4H), 3.92 (t,J=4.4 Hz, 4H), 5.20 (s, 2H), 7.28-7.32 (m, 2H), 7.46 (s, 1H), 8.41-8.45(m, 2H), 8.74 (s, 2H), 9.05 (s, 1H), 11.12 (s, 1H).

Example 76 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-p-tolylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 201)

Step 76a: Ethyl2-(methyl((4-morpholino-2-p-tolylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-201)

The title compound 0603-201 was prepared (306 mg, 78%) as a white solidfrom 0504-54 (350 mg, 0.78 mmol), 4-methylphenylboronic acid (212 mg,1.56 mmol), Pd(PPh₃)₂Cl₂ (27 mg, 0.039 mmol), NaHCO₃ (196 mg, 2.34 mmol)in toluene (8 mL), ethanol (5 mL), and water (2 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 505[M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.31 (t, J=7.0 Hz, 3H), 2.34 (s, 3H),3.23 (s, 3H), 3.79 (t, J=4.8 Hz, 4H), 3.93 (t, J=4.8 Hz, 4H), 4.29 (q,J=7.2 Hz, 2H), 5.12 (s, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.31 (s, 1H), 8.24(d, J=8.0 Hz, 2H), 8.86 (s, 2H).

Step 76b:N-Hydroxy-2-(methyl((4-morpholino-2-p-tolylthieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 201)

The title compound 201 was prepared (27 mg, 9%) as a off-white solidfrom 0603-201 (306 mg, 0.61 mmol) and freshly prepared hydroxylaminemethanol solution (16 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p.: 170-172° C. LCMS: 492 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆):δ 2.35 (s, 3H), 3.22 (s, 3H), 3.75 (m, 4H), 3.90 (m,4H), 5.19 (s, 2H), 7.27 (d, J=7.6 Hz, 2H), 7.43 (s, 1H), 8.27 (d, J=8.4Hz, 2H), 8.73 (s, 2H).

Example 77 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 202)

Step 77a: Ethyl2-(methyl((4-morpholino-2-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-202)

The title compound 0603-202 was prepared (527 mg, crude) as a whitesolid from 0504-54 (350 mg, 0.78 mmol), 4-trifluoromethylphenylboronicacid (296 mg, 1.56 mmol), Pd(PPh₃)₂Cl₂ (27 mg, 0.039 mmol), NaHCO₃ (196mg, 2.34 mmol) in toluene (8 mL), ethanol (5 mL), and water (2 mL) usinga procedure similar to that described for compound 0603-107 (Example34). LCMS: 559 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 1.32 (t, J=7.0 Hz,3H), 3.24 (s, 3H), 3.81 (t, J=4.8 Hz, 4H), 3.96 (t, J=4.6 Hz, 4H), 4.30(q, J=7.1 Hz, 2H), 5.12 (s, 2H), 7.34 (s, 1H), 7.63 (d, J=8.4 Hz, 2H),8.45 (d, J=8.0 Hz, 2H), 8.86 (s, 2H).

Step 77b:N-Hydroxy-2-(methyl((4-morpholino-2-(4-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 202)

The title compound 202 was prepared (162 mg, 38%) as anoff-white solidfrom 0603-202 (527 mg, crude) and freshly prepared hydroxylaminemethanol solution (16 mL) using a procedure similar to that describedfor compound 3 (Example 1). m.p. 222-223° C. LCMS: 546 [M+1]⁻; ¹H NMR(400 MHz, DMSO-d₆): δ 3.23 (s, 3H), 3.76 (t, J=4.4 Hz, 4H), 3.94 (t,J=4.2 Hz, 4H), 5.21 (s, 2H), 7.50 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 8.57(d, J=8.4 Hz, 2H), 8.74 (s, 2H), 9.06 (s, 1H), 11.13 (s, 1H).

Example 78 Preparation of N-hydroxy-2-(methyl((2-(4-(methylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 151)

Step 78a: 4-Bromo-N-methylbenzenamine (Compound 0601-151) and4-bromo-N,N-dimethylbenzenamine (Compound 0601-152)

To a solution of 4-bromobenzenamine (3 g, 17.4 mmol) and K₂CO₃ (3.62 g,26.2 mmol) in THF (30 mL) was added methyl iodide (2.2 ml, 34.8 mmol) atroom temperature and stirred overnight. Water (6 mL) was added to thereaction mixture and the mixture was extracted with ethyl acetate (50mL×3). The organic layer was dried, concentrated and purified by columnchromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v)to give 0601-151 (840 mg, 26%) as a white solid LCMS: 187 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.63 (s, 3H), 5.85 (br, 1H), 6.48 (d, J=9.2 Hz,2H), 7.20 (d, J=8.4 Hz, 2H) and 0601-152 (680 mg, 20%) as a white solid.LCMS: 201 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.87 (s, 6H), 6.65 (d,J=9.2 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H).

Step 78b:N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine(Compound 0602-151)

The title compound 0602-151 was prepared (301 mg, 60%) as a white solidfrom 0601-151 (400 mg, 2.15 mmol), bis(pinacolato)diboron (819 mg, 3.23mmol), potassium acetate (632 mg, 6.4 mmol) and Pd(dppf)₂Cl₂ (351 mg,0.43 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 234 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.24 (s, 12H), 2.67 (d, J=5.2 Hz, 3H), 6.04 (br, 1H), 6.48 (d, J=8.4 Hz,2H), 7.39 (d, J=8.4 Hz, 2H).

Step 78c: Ethyl2-(methyl((2-(4-(methylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-151)

The title compound 0603-151 was prepared (100 mg, 64%) as a white solidfrom 0504-54 (135 mg, 0.3 mmol), 0602-151 (100 mg, 0.42 mmol),Pd(PPh₃)₂Cl₂ (10.5 mg, 0.015 mmol), NaHCO₃ (76 mg, 0.9 mmol) in toluene(2.5 mL), ethanol (1.6 mL), and water (0.7 mL) using a procedure similarto that described for compound 0603-107 (Example 34). LCMS: 520 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 2.73 (d, J=4.8 Hz,3H), 3.26 (s, 3H), 3.75 (m, 4H), 3.88 (m, 4H), 4.29 (q, J=7.2 Hz, 2H),5.21 (s, 2H), 6.10 (m, 1H), 6.58 (d, J=8.8 Hz, 2H), 7.39 (s, 1H), 8.15(d, J=8.4 Hz, 2H), 8.88 (d, J=4.8 Hz, 2H).

Step 78d:N-hydroxy-2-(methyl((2-(4-(methylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 151)

The title compound 151 was prepared (40 mg, 42%) as a yellow solid from0603-151 (100 mg, 0.19 mmol) and freshly prepared hydroxylamine methanolsolution (6 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 218-220° C. LCMS: 507 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 2.73 (d, J=4.4 Hz, 3H), 3.75 (d, J=4.0 Hz, 4H), 3.87 (d,J=4.0 Hz, 4H), 5.18 (s, 2H), 6.11 (d, J=4.8 Hz, 1H), 6.58 (d, J=8.0 Hz,2H), 7.37 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.75 (s, 2H), 9.06 (s, 1H),11.13 (br, 1H).

Example 79 Preparation of2-(((2-(4-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 152)

Step 79a:N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine(Compound 0602-152)

The title compound 0602-152 was prepared (360 mg, 61%) as a white solidfrom 0601-152 (480 mg, 2.4 mmol), bis(pinacolato)diboron (914 mg, 3.6mmol), potassium acetate (706 mg, 7.2 mmol) and Pd(dppf)₂Cl₂ (390 mg,0.48 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 248 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.25 (s, 12H), 2.93 (s, 6H), 6.66 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz,2H).

Step 79b: Ethyl2-(((2-(4-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-152)

The title compound 0603-152 was prepared (100 mg, 53%) as a white solidfrom 0504-54 (161 mg, 0.36 mmol), 0602-152 (150 mg, 0.61 mmol),Pd(PPh₃)₂Cl₂ (13 mg, 0.018 mmol), NaHCO₃ (91 mg, 1.08 mmol) in toluene(2.5 mL), ethanol (1.6 mL), and water (0.7 mL) using a procedure similarto that described for compound 0603-107 (Example 34). LCMS: 534 [M+1]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (m, 3H), 2.97 (s, 6H), 3.22 (s, 3H),3.74 (m, 4H), 3.87 (m, 4H), 4.14 (m, 2H), 5.17 (s, 2H), 6.75 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 8.20 (d, J=9.2 Hz, 2H), 8.73 (s, 2H).

Step 79c:2-(((2-(4-(dimethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 152)

The title compound 152 was prepared (30 mg, 30%) as a yellow solid from0603-152 (100 mg, 0.19 mmol) and freshly prepared hydroxylamine methanolsolution (6 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 208-210° C. LCMS: 521 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 2.98 (s, 6H), 3.23 (s, 3H), 3.76 (d, J=4.0 Hz, 4H), 3.89 (s,4H), 5.18 (s, 2H), 6.76 (d, J=8.8 Hz, 2H), 7.39 (s, 1H), 8.22 (d, J=8.4Hz, 2H), 8.75 (s, 2H), 9.07 (br, 1H).

Example 80 Preparation of2-(((2-(4-(ethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 153)

Step 80a: 4-Bromo-N-ethylbenzenamine (Compound 0601-153)

To a solution of 4-bromobenzenamine (2.00 g, 11.67 mmol) and iodoethane(5.50 g, 35.28 mmol) in CH₃CN (50 mL) was added K₂CO₃ (6.48 g, 47.04mmol). The mixture was stirred at 60° C. overnight. The reaction mixturewas concentrated in vacuo and the residue was purified by columnchromatography on silica gel (ethyl acetate in petroleum ether, 0%-10%v/v) to give compound 0601-153 (800 mg, 38%) as a light yellow oil.LCMS: 200 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.13 (t, J=6.8 Hz, 3H),2.97 (m, 2H), 5.73 (br s, 1H), 6.48 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8Hz, 2H).

Step 80b:N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine(Compound 0602-153)

The title compound 0602-153 was prepared (640 mg, 72%) as a white solidfrom 0601-153 (884 mg, 4.420 mmol), bis(pinacolato)diboron (1.68 g,6.630 mmol), potassium acetate (1.30 g, 13.3mmol) and Pd(dppf)₂Cl₂ (362mg, 0.44 mmol) using a procedure similar to that described for compound0602-107 (Example 34). LCMS: 248 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ1.13 (m, 15H), 3.03 (m, 2H), 5.94 (br s, 1H), 6.49 (d, J=8.4 Hz, 2H),7.37 (d, J=8.8 Hz, 2H).

Step 80c: Ethyl2-(((2-(4-(ethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-153)

The title compound 0603-153 was prepared (200 mg, 71%) as a white solidfrom 0504-54 (240 mg, 0.53 mmol), 0602-153 (172 mg, 0.69 mmol),Pd(PPh₃)₂Cl₂ (37 mg, 0.053 mmol), NaHCO₃ (134 mg, 1.6 mmol) in toluene(8 mL), ethanol (5 mL), and water (2 mL) using a procedure similar tothat described for compound 0603-107 (Example 34). LCMS: 534 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 1.17 (t, J=7.2 Hz, 3H), 2.29 (t, J=7.6 Hz,3H), 3.09 (m, 2H), 3.25 (s, 3H), 3.73 (br s, 4H), 3.87 (br s, 4H), 4.27(m, 2H), 5.20 (s, 2H), 6.02 (t, J=4.8 Hz, 1H), 6.58 (d, J=8.8 Hz, 2H),7.37 (s, 1H), 8.12 (d, J=8.8 Hz, 2H), 8.87 (s, 2H). P49

Step 80d:2-(((2-(4-(Ethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 153)

The title compound 153 was prepared (110 mg, 56%) as an off-white solidfrom 0603-153 (200 mg, 0.38 mmol) and freshly prepared hydroxylaminemethanol solution (8 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 185-187° C.; LCMS: 521 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆): δ 1.18 (t, J=6.8 Hz, 3H), 3.09 (m, 2H), 3.23 (s, 3H),3.75 (br s, 4H), 3.87 (br s, 4H), 5.18 (s, 2H), 6.02 (t, J=4.8 Hz, 1H),6.59 (d, J=8.8 Hz, 2H), 7.36 (s, 1H), 8.13 (d, J=8.4 Hz, 2H), 8.74 (s,2H), 9.06 (s, 1H), 11.13 (s, 1H).

Example 81 Preparation of2-(((2-(4-(Diethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 154)

Step 81a: 4-Bromo-N,N-diethylbenzenamine (Compound 0601-154)

The title compound 0601-154 (1.10 g, 40%) was synthesized according tothe synthetic procedure of making compound 0601-153 using4-bromobenzenamine (2.00 g, 11.67 mmol) and iodoethane (5.50 g, 35.28mmol) as starting material. LCMS: 228 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆):δ 1.05 (t, J=7.2 Hz, 6H), 3.30 (m, 4H), 6.58 (d, J=8.8 Hz, 2H), 7.22 (d,J=8.8 Hz, 2H).

Step 81b:N,N-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine(Compound 0602-154)

The title compound 0602-154 was prepared (860 mg, 63%) as a white solidfrom 0601-154 (1.21 g, 5.33 mmol), bis(pinacolato)diboron (2.03 g, 8.00mmol), potassium acetate and Pd(dppf)₂Cl₂ using a procedure similar tothat described for compound 0602-107 (Example 34). LCMS: 276 [M+1]⁻; ¹HNMR (400 MHz, DMSO-d₆): δ 1.06 (t, J=6.8 Hz, 6H), 1.24 (s, 12H), 3.34(m, 4H), 6.60 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H).

Step 81c: Ethyl2-(((2-(4-(diethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-154)

The title compound 0603-154 was prepared (260 mg, 85%) as a white solidfrom 0504-54 (240 mg, 0.53 mmol), 0602-154 (220 mg, 0.8 mmol),Pd(PPh₃)₂Cl₂, NaHCO₃ in toluene (8 mL), ethanol (5 mL), and water (2 mL)using a procedure similar to that described for compound 0603-107(Example 34). LCMS: 562 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.12 (t,J=7.2 Hz, 6H), 1.29 (t, J=6.8 Hz, 3H), 3.25 (s, 3H), 3.40 (m, 4H), 3.74(br s, 4H), 3.87 (br s, 4H), 4.27 (m, 2H), 5.20 (s, 2H), 6.69 (d, J=8.8Hz, 2H), 7.39 (s, 1H), 8.18 (d, J=8.8 Hz, 2H), 8.87 (s, 2H).

Step 81d:2-(((2-(4-(Diethylamino)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 154)

The title compound 154 was prepared (180 mg, 71%) as an off-white solidfrom 0603-154 (260 g, 0.463 mmol) and freshly prepared hydroxylaminemethanol solution (8 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 192-196° C.; LCMS: 549 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆): δ 1.12 (t, J=7.2 Hz, 6H), 3.23 (s, 3H), 3.41 (m, 4H),3.75 (br s, 4H), 3.87 (br s, 4H), 5.18 (s, 2H), 6.70 (d, J=8.8 Hz, 2H),7.37 (s, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.74 (s, 2H), 9.06 (s, 1H), 11.11(s, 1H).

Example 82 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(4-(pyrrolidin-1-yl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 155)

Step 82a: 1-(4-Bromophenyl)pyrrolidine (Compound 0601-155)

A mixture of 4-bromoaniline (1 g, 5.81 mmol), Cs₂CO₃ (5.68 g, 17.44mmol), 1,4-dibromobutane (1.88 g, 8.72 mmol) in DMF (20 mL) was stirredat 60° C. overnight. After cooled to room temperature, the mixture wasdiluted with water (200 mL) and extracted with ethyl acetate (2×100 mL).The organic layer was washed with water (3×100 mL) and brine (100 mL),dried over Na₂SO₄, concentrated and purified by column chromatography onsilica gel (petroleum ether) to give compound 0601-155 (720 mg, 46%) asa colorless oil. LCMS: 226 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.94 (t,J=6.4 Hz, 4H), 3.18 (t, J=6.4 Hz, 4H), 6.47 (d, J=9.2 Hz, 1H), 7.27 (d,J=9.2 Hz, 1H).

Step 82b:1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidineate(Compound 0602-155)

The title compound 0602-155 was prepared (500 mg, 57%) as a yellow solidfrom 0601-155 (720 mg, 3.18 mmol), bis(pinacolato)diboron (1.21 g, 4.78mmol), AcOK (938 mg, 9.56 mmol), PdCl₂(dppf)₂ (78 mg, 0.0956 mmol) usinga procedure similar to that described for compound 0602-107 (Example34). LCMS: 274 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 (s, 12H), 1.95(t, J=6.8 Hz, 4H), 3.23 (t, J=6.4 Hz, 4H), 6.49 (d, J=8.8 Hz, 1H), 7.46(d, J=8.4 Hz, 1H).

Step 82c: Ethyl2-(methyl((4-morpholino-2-(4-(pyrrolidin-1-yl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-155)

The title compound 0603-155 was prepared (320 mg, 86%) as a yellow solidfrom 0504-54 (300 mg, 0.668 mmol), 0602-155 (219 mg, 0.80 mmol), NaHCO₃(168 mg, 2.00 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.033 mmol) in ethanol (2.3mL), toluene (4 mL) and water (1 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 560 [M+1]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.30 (t, J=7.6 Hz, 3H), 1.98 (m, 4H), 3.26 (s, 3H),3.30 (m, 4H), 3.75 (m, 4H), 3.90 (m, 4H), 4.29 (q, J=6.8 Hz, 2H), 5.22(s, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.40 (s, 1H), 8.21 (d, J=8.8 Hz, 2H),8.88 (s, 2H).

Step 82d:N-Hydroxy-2-(methyl((4-morpholino-2-(4-(pyrrolidin-1-yl)phenyl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 155)

The title compound 155 was prepared (55 mg, 28%) as a yellow solid from0603-155 (200 mg, 0.49 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). mp. 187-192° C. LCMS: 547 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 1.97 (m, 4H), 3.23 (s, 3H), 3.30 (m, 4H), 3.76 (m, 4H),3.88 (m, 4H), 5.18 (s, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 8.21(d, J=8.4 Hz, 2H), 8.75 (s, 2H), 9.06 (s, 1H), 11.12 (s, 1H).

Example 83 Preparation of2-(((2-(3,4-diaminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 156)

Step 83a:4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine(Compound 0602-156)

The title compound 0602-156 was prepared (1.0 g, 43%) as a yellow solidfrom 4-bromobenzene-1,2-diamine (1.87 g, 10 mmol),bis(pinacolato)diboron (3.9 g, 15 mmol), Pd(dppf)₂Cl₂ (817 mg, 1 mmol)and AcOK (2.9 g, 30 mmol) using a procedure similar to that describedfor compound 0602-107 (Example 34). LCMS: 235 [M+1]⁺, ¹H NMR (400 MHz,DMSO-d₆) δ 1.23 (s, 12H), 4.38 (s, 2H), 4.82 (s, 2H), 6.46 (d, J=7.6 Hz,1H), 6.77 (dd, J=7.6, 0.8 Hz, 1H), 6.88 (d, J=0.8 Hz, 1H).

Step 83b: Ethyl2-(((2-(3,4-diaminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-156)

The title compound 0603-156 was prepared (300 mg, 86%) as a white solidfrom 0504-54 (300 mg, 0.67 mmol), 0602-156 (190 mg, 0.80 mmol), NaHCO₃(169 mg, 2.0 mmol), CsF (203 mg, 1.34 mmol), (Ph₃P)₂PdCl₂ (47 mg, 0.067mmol) in toluene (4 mL), ethanol (2 mL) and water (0.5 mL) using aprocedure similar to that described for compound 0603-107 (Example 34).LCMS: 521 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t, J=7.2 Hz, 3H),3.26 (s, 3H), 3.75 (m, 4H), 3.87 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 4.55(s, 2H), 4.89 (s, 2H), 5.21 (s, 2H), 6.54 (d, J=8.4 Hz, 1H), 7.36 (s,1H), 7.52 (dd, J=8.4, 2.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 8.88 (s, 2H).

Step 83c:2-(((2-(3,4-diaminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 156)

The title compound 156 was prepared (128 mg, 44%) as a yellow solid from0603-156 (300 mg, 0.58 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 222-225° C. LCMS: 508 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 3.21 (s, 3H), 3.75 (m, 4H), 3.87 (m, 4H), 4.54 (s, 2H),4.88 (s, 2H), 5.14 (s, 2H), 6.53 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.52(d, J=7.6 Hz, 1H), 7.62 (s, 1H), 8.73 (s, 2H).

Example 84 Preparation of2-(((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 176)

Step 84a: Tert-butyl 4-bromo-1H-indole-1-carboxylate (Compound 0601-176)

The solution of 4-bromoindole (394 mg, 2.00 mmol), (Boc)₂O (523 mg, 2.40mmol), DMAP (293 mg, 2.4 mmol) and Et₃N (0.4 mL) in MeCN (6 mL) wasstirred at room temperature for 2 hours. The solvent was removed and theresidue was dissolved in ethyl acetate (40 mL), washed with water (3×20mL) and brine (1×20 mL), the organic layer was concentrated and purifiedby column chromatography on silica gel (petroleum ether) to affordcompound 0601-176 (508 mg, 85%) as a colorless oil. ¹H-NMR (400 MHz.DMSO-d₆) δ 1.64 (s, 9H), 6.67 (d, J=3.2 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H),7.48 (m, 1H), 7.80 (d, J=3.2 Hz, 1H), 8.08 (m, 1H).

Step 84b: Tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(Compound 0602-176)

The title compound 0602-176 was prepared (448 mg, 77%) as a white solidfrom 0601-176 (503 mg, 1.69 mmol), bis(pinacolato)diboron (644 mg, 2.54mmol), Pd(dppf)₂Cl₂ (138 mg, 0.17 mmol) and AcOK (497 mg, 5.07 mmol)using a procedure similar to that described for compound 0602-107(Example 34). ¹H-NMR (400 MHz. DMSO-d₆) δ 1.34 (s, 12H), 1.64 (s, 9H),6.98 (d, J=2.8 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.58 (m, 1H), 7.72 (d,J=2.8 Hz, 1H), 8.20 (m, 1H).

Step 84c: Ethyl2-(((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-176)

The compound tert-butyl4-(6-(((5-(ethoxycarbonyl)pyrimidin-2-yl)(methyl)amino)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indole-1-carboxylatewas prepared (368 mg, 59%) as a white solid from 0504-54 (448 mg, 1.00mmol), 0602-176 (343 mg, 1.00 mmol), Cs₂CO₃ (652 mg, 2.00 mmol) andPd(dppf)₂Cl₂ (82 mg, 0.10 mmol) in 1,4-dioxane (6 mL) and water (0.2 mL)using a procedure similar to that described for compound 0603-107(Example 34). LCMS: 630 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.30 (t,J=7.2 Hz, 3H), 1.65 (s, 9H), 3.28 (s, 3H), 3.78 (m, 4H), 3.93 (m, 4H),4.29 (q, J=7.2 Hz, 2H), 5.25 (s, 2H), 7.44 (m, 1H), 7.55 (s, 1H), 7.72(m, 1H), 7.77 (m, 1H), 8.25 (m, 2H), 8.88 (s, 2H).

A mixture of above solid (368 mg, 0.59 mmol) trifluoroacetic acid (4 mL)was stirred at room temperature for 1 hour. Adjusted to pH7 with 10%aqueous NaOH, and extracted with CH₂Cl₂ (60 mL). The organic layer waswashed with brine (1×30 mL), dried and concentrated to get compound0603-176 (312 mg, 100%) as a yellow solid. LCMS: 530 [M+1]⁺. ¹H-NMR (400MHz. DMSO-d₆) δ 1.31 (t, J=6.8 Hz, 3H), 3.29 (s, 3H), 3.79 (m, 4H), 3.94(m, 4H), 4.30 (q, J=7.2 Hz, 2H), 5.26 (s, 2H), 7.19 (t, J=8.0 Hz, 1H),7.43 (m, 2H), 7.53 (s, 1H), 8.11 (m, 1H), 8.89 (s, 2H), 11.23 (s, 1H).

Step 84d:2-(((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 176)

The title compound 176 was prepared (78 mg, 25%) as a white solid from0603-176 (318 mg, 0.60 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 200-212° C. LCMS: 517 [M+1]⁻. ¹H-NMR (400MHz. DMSO-d6) δ 3.26 (s, 3H), 3.79 (m, 4H), 3.94 (m, 4H), 5.22 (s, 2H),7.19 (t, J=8.0 Hz, 1H), 7.43 (m, 2H), 7.52 (m, 2H), 8.12 (d, J=8.0 Hz,1H), 8.77 (s, 2H), 9.07 (s, 1H), 11.14 (s, 1H), 11.24 (s, 1H).

Example 85 Preparation ofN-hydroxy-2-(((2-(indolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 177)

Step 85a: Tert-butyl 4-bromoindoline-1-carboxylate (Compound 0601-177)

A mixture of 4-bromooxindole (2.77 g, 0.01 mol) and a solution of BH₃ inTHF (2 M, 40 mL) was stirred at room temperature overnight. The mixturewas cooled to 0° C. and diluted with 30 mL of methanol, followed byaddition of 12 N HCl (7.5 mL). The resulting mixture was stirred at roomtemperature for 1 hour, adjusted to pH 8-9 with 10% aqueous NaOH. Waterwas added to the mixture and extracted with ethyl acetate (3×100 mL).The organic layer was dried and concentrated to get the crude productwhich was washed through a silica gel column (ethyl acetate in petroleumether (10%). The crude product was dissolved in 10% HCl (3×10 mL). Theaqueous layer was adjusted to pH7 with NaHCO₃, extracted with ethylacetate (3×20 mL). The organic layer was dried and concentrated to get4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+1]⁺. ¹H-NMR (400MHz. DMSO-d₆) δ 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s,1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H).

A mixture of above obtained 4-bromoindoline (759 mg, 3.81 mmol), and(Boc)₂O (976 mg, 4.48 mmol) in MeCN (8 mL) was stirred at roomtemperature overnight. After evaporated, the residue was dissolved inethyl acetate (40 mL), washed with water (3×20 mL) and brine (1×20 mL).The organic layer was concentrated and purified by column chromatographyon silica gel (petroleum ether) to give 0601-177 (840 mg, 74%) as awhite solid. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.50 (s, 9H), 3.02 (t, J=8.8Hz, 2H), 3.94 (t, J=8.8 Hz, 2H), 7.12 (m, 2H), 7.56 (m, 1H).

Step 85b: Tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline -1-carboxylate(Compound 0602-177)

The title compound 0602-177 was prepared (814 mg, 84%) as a white solidfrom 0601-177 (840 mg, 2.81 mmol), bis(pinacolato)diboron (1.07 g, 4.21mmol), Pd(dppf)₂Cl₂ (229 mg, 0.28 mmol) and AcOK (826 mg, 8.43 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 290 [M−55]⁺; ¹H-NMR (400 MHz. DMSO-d₆) δ 1.35 (s,12H), 1.57 (s, 9H), 3.24 (t, J=8.4 Hz, 2H), 3.94 (t, J=8.4 Hz, 2H), 7.20(m, 1H), 7.28 (m, 1H), 7.88 (m, 1H).

Step 85c: Ethyl2-(((2-(indolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-177)

Compound tert-butyl4-(6-(((5-(ethoxycarbonyl)pyrimidin-2-yl)(methyl)amino)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)indoline-1-carboxylatewas prepared (463 mg, 73%) as a white solid from 0504-54 (448 mg, 1.00mmol), 0602-177 (345 mg, 1.00 mmol), Cs₂CO₃ (652 mg, 2.00 mmol) andPd(dppf)₂Cl₂ (82 mg, 0.10 mmol) in 1,4-dioxane (6 mL) and water (0.2 mL)using a procedure similar to that described for compound 0603-107(Example 34). LCMS: 632 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.30 (t,J=7.2 Hz, 3H), 1.52 (s, 9H), 3.27 (s, 3H), 3.55 (m, 2H), 3.87 (m, 4H),3.94 (m, 6H), 4.29 (q, J=7.2 Hz, 2H), 5.23 (s, 2H), 7.26 (m, 1H), 7.46(s, 1H), 7.81 (m, 1H), 7.89 (m, 1H), 8.87 (s, 2H).

A mixture of above product (463 mg, 0.73 mmol) and trifluoroacetic acid(4 mL) was stirred at room temperature for 1 hour. The mixture wasadjusted to pH 7 with 10% aqueous NaOH, extracted with CH₂Cl₂ (60 mL).The organic layer was washed with brine (1×30 mL), dried andconcentrated to give 0603-177 (283 mg, 73%) as an off-white solid. LCMS:532 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H), 3.27 (s,3H), 3.41 (m, 4H), 3.75 (m, 4H), 3.86 (m, 4H), 4.29 (q, J=6.8 Hz, 2H),5.23 (s, 2H), 5.58 (s, 1H), 6.58 (m, 1H), 7.01 (t, J=8.0 Hz, 1H), 7.47(m, 2H), 8.88 (s, 2H).

Step 85d:N-Hydroxy-2-(((2-(indolin-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxamide(Compound 177)

The title compound 177 was prepared (130 mg, 49%) as a white solid from0603-177 (273 mg, 0.51 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 146-156° C. LCMS: 519 [M+1]⁺. ¹H-NMR (400 MHz.DMSO-d₆) δ 3.24 (s, 3H), 3.42 (m, 4H), 3.75 (m, 4H), 3.87 (m, 4H), 5.20(s, 2H), 5.57 (s, 1H), 6.58 (m, 1H), 7.01 (t, J=8.0 Hz, 1H), 7.43 (s,1H), 7.48 (m, 1H), 8.76 (s, 2H), 9.07 (s, 1H), 11.13 (s, 1H).

Example 86 Preparation of2-(((2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 182)

Step 86a: Tert-butyl6-bromo-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylate (Compound0601-182)

A mixture of compound 4-bromo-2-nitrophenol (1 g, 4.59 mmol) and SnCl₂(5.2 g, 22.9 mmol) in ethanol (10 mL) was stirred at 70° C. for 2 h.After cooled down, the mixture was diluted with water (100 mL), adjustedto pH 7 with saturated aqueous NaHCO₃ and extracted with ethyl acetate(100 mL). The organic layer was washed with brine (50 mL), dried overNa₂SO₄, concentrated to give 2-amino-4-bromophenol (770 mg, 89%) as agrey solid. LCMS: 188 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 4.79 (s, 2H),6.48 (dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.71 (d,J=2.4 Hz, 1H), 9.26 (s, 1H).

A mixture of the product 2-amino-4-bromophenol (500 mg, 2.66 mmol),1,2-dibromoethane (2.5 g, 13.3 mmol) and K₂CO₃ (1.84 g, 13.3 mmol) inDMF (10 mL) was stirred at room temperature for 4 h. The mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (100 mL).The organic layer was washed with water (3×50 mL) and brine (50 mL),concentrated and purified by column chromatography on silica gel (ethylacetate in petroleum, 10% v/v) to give5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 37%) as a yellow solid.LCMS: 294 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.79 (t, J=6.0 Hz, 2H),4.25 (t, J=5.6 Hz, 2H), 5.06 (s, 2H), 6.63 (dd, J₁=2.4 Hz, J₂=8.0 Hz,1H), 6.77 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H).

A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg,0.848 mmol) and K₂CO₃ (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at60° C. for 4 h. The mixture was diluted with water (100 mL) andextracted with ethyl acetate (100 mL). The organic layer was washed withwater (3×50 mL) and brine (50 mL), concentrated to give6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (170 mg, 94%) as a yellowoil. LCMS: 214 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.26 (m, 2H), 4.08(t, J=4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J=1.6 Hz, 1H).

A mixture of the product 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine(1.37 g, 6.4 mmol), Boc₂O (1.676 g, 7.68 mmol), Et₃N (970 mg, 9.6 mmol),DMAP (78 mg, 0.64 mmol) in THF (27 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with water (200 mL) andextracted with ethyl acetate (100 mL). The organic layer was washed withwater (50 mL) and brine, dried over Na₂SO₄ and concentrated to givecompound 0601-182 (1.3 g, 65%) as a yellow oil. LCMS: 258 [M−55]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 1.49 (s, 9H), 3.78 (t, J=4.8 Hz, 2H), 4.21 (t,J=4.4 Hz, 2H), 6.83 (d, J=4.4 Hz, 1H), 7.12 (dd, J₁=2.0 Hz, J₂=8.4 Hz,2H), 8.01 (s, 1H).

Step 86b: Tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylate(Compound 0602-182)

The title compound 0602-182 was prepared (1.4 g, 98%) as a oil from0601-182 (1.16 g, 3.69 mmol), bis(pinacolato)diboron (1.41 g, 5.54mmol), Pd(dppf)₂Cl₂ (90 mg, 0.111 mmol) and AcOK (1.09 g, 11.07 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 306 [M−55]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.27 (s,12H), 1.49 (s, 9H), 3.79 (t, J=4.4 Hz, 2H), 4.23 (t, J=4.0 Hz, 2H), 6.88(d, J=8.0 Hz, 1H), 7.25 (d, J=9.6 Hz, 2H), 8.13 (s, 1H).

Step 86c: Ethyl2-(((2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-182)

Compound tert-butyl6-(6-(((5-(ethoxycarbonyl)pyrimidin-2-yl)(methyl)amino)methyl)-4-morpholinothieo[3,2-d]pyrimidin-2-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylatewas prepared (250 mg, 58%) as a yellow solid from 0504-54 (300 mg, 0.668mmol), 0602-182 (290 mg, 0.802 mmol), NaHCO₃ (168 mg, 2.00 mmol),(Ph₃P)₂PdCl₂ (23 mg, 0.0334 mmol) in ethanol (2.3 mL), toluene (4 mL)and water (1 mL) using a procedure similar to that described forcompound 0603-107 (Example 34). LCMS: 648 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H), 1.52 (s, 9H), 3.26 (s, 3H), 3.75 (m,4H), 3.83 (m, 2H), 3.92 (m, 4H), 4.28 (m, 4H), 5.23 (s, 2H), 6.93 (d,J=8.4 Hz, 1H), 7.45 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.80 (s, 1H), 8.88(s, 2H).

To a solution of the above prepared compound (250 mg, 0.386 mmol) indichloromethane (25 ml) was added CF₃COOH (2.5 mL) and stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (100mL) and washed with saturated aqueous NaHCO₃ (50 mL), water (100 mL) andbrine (50 mL), dried over Na₂SO₄, concentrated to give 0603-182 (200 mg,95%) as a yellow solid. LCMS: 548 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.30 (t, J=7.2 Hz, 3H), 3.26 (s, 3H), 3.30 (m, 2H), 3.75 (m, 4H), 3.89(m, 4H), 4.17 (m, 2H), 4.28 (q, J=7.2 Hz, 2H), 5.22 (s, 2H), 5.92 (s,1H), 6.70 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.56 (d, J=10.0 Hz, 1H), 7.68(s, 1H), 8.88 (s, 2H).

Step 86d:2-(((2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 182)

The title compound 182 was prepared (72 mg, 37%) as a white solid from0603-182 (200 mg, 0.365 mmol) and freshly prepared hydroxylaminemethanol solution (10 mL) using a procedure similar to that describedfor compound 3 (Example 1). mp. 170-183° C. LCMS: 535 [M+H]⁻. ¹H NMR(400 MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.30 (m, 2H), 3.75 (m, 4H), 3.89 (m,4H), 4.17 (m, 2H), 5.19 (s, 2H), 5.91 (s, 1H), 6.70 (d, J=8.0 Hz, 1H),7.40 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 8.75 (s, 2H), 9.07(s, 1H), 11.01 (s, 1H).

Example 87 Preparation of2-(((2-(1H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 187)

Step 87a: Tert-butyl 5-bromo-1H-benzo[d]imidazole-1-carboxylate(Compound 0601-187)

To a solution of 4-bromobenzene-1,2-diamine (3 g, 16 mmol) in DMF (22mL) were added trimethyl orthoformate (44 mL) and conc. HCl (1.5 mL) andthe mixture was stirred at room temperature for 1 h. The mixture wasdiluted with water (200 mL) and adjusted to pH7 with saturated aqueousNaHCO₃, extract with ethyl acetate (200 mL). The organic layer was driedover Na₂SO₄, concentrated to give 5-bromo-1H-benzo[d]imidazole (3.25 g,100%) as an off-white solid. LCMS: 197 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 7.33 (t, J=8.8 Hz, 1H), 7.55 (dd, J₁=7.6 Hz, J=40 Hz, 1H), 7.79 (d,J=47.2 Hz, 1H), 8.26 (s, 1H), 12.61 (d, J=25.6 Hz, 1H).

To a solution of above prepared 5-bromo-1H-benzo[d]imidazole (3.25 g,22.1 mmol) in THF (65 mL) was added Boc₂O (5.79 g, 26.5 mmol), Et₃N(3.35, 33.15 mmol) and DMAP (270 mg, 2.21 mmol). The mixture was stirredat room temperature for 4 h, diluted with water (200 mL), extracted withethyl acetate (200 mL). The organic layer was washed with water (2×100mL) and brine (100 mL), dried over Na₂SO₄, concentrated to give 0601-187(4.8 g, 98%) as a oil. LCMS: 241 [M−55]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.65 (s, 9H), 7.57 (dd, J₁=8.4 Hz, J₂=20 Hz, 1H), 7.73 (d, J=8.4 Hz,1H), 7.88 (d, J=9.2 Hz, 1H), 8.03 (d, J=35.6 Hz, 1H), 8.70 (d, J=8.0 Hz,1H).

Step 87b: Tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate(Compound 0602-187)

The title compound 0602-187 was prepared (0.94 g, 81%) as a colorlessoil from 0601-187 (1 g, 3.37 mmol), bis(pinacolato)diboron (1.28 g, 5.05mmol), Pd(dppf)₂Cl₂ (82 mg, 0.101 mmol) and AcOK (991 mg, 10.1 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 289 [M−55]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32 (s,12H), 1.65 (s, 9H), 7.65 (d, J=7.2 Hz, 0.5H), 7.74 (t, J=8.4 Hz, 1H),7.97 (d, J=8.4 Hz, 1H), 8.37 (s, 0.5H), 8.69 (d, J=18.8 Hz, 1H).

Step 87c: Ethyl2-(((2-(1H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylate(Compound 0603-187)

The compound 0603-187 was prepared (260 mg, 62%) as a yellow solid from0504-54 (300 mg, 0.668 mmol), 0602-187 (276 mg, 0.8 mmol), NaHCO₃ (168mg, 2.00 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.0334 mmol) in ethanol (2.3 mL),toluene (4 mL) and water (1 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 531 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 3.28 (s, 3H), 3.78 (m, 4H),3.95 (m, 4H), 4.29 (q, J=6.8 Hz, 2H), 5.24 (s, 2H), 7.50 (s, 1H), 7.65(d, J=8.0 Hz, 1H), 8.32 (m, 2H), 8.64 (s, 1H), 8.88 (s, 2H), 12.59 (s,1H).

Step 87d:2-(((2-(1H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide(Compound 187)

The title compound 187 was prepared (34 mg, 13%) as a yellow solid from0603-187 (260 mg, 0.49 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). mp. 231-239° C. LCMS: 518 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.25 (s, 3H), 3.79 (m, 4H), 3.95 (m, 4H), 5.21 (s, 2H),7.48 (s, 1H), 7.65 (dd, J₁=8.4 Hz, J₂=47.2 Hz, 1H), 8.31 (m, 2H), 8.64(d, J=44.8 Hz, 1H), 8.76 (s, 2H), 9.09 (s, 1H), 11.03 (s, 1H), 12.59 (s,1H).

Example 88 Preparation ofN-hydroxy-2-(methyl((2-(2-methyl-3H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 199)

Step 88a: N,N′-(4-bromo-1,2-phenylene)diacetamide (Compound 0601-199)

To the solution of 4-bromobenzene-1,2-diamine (1.87 g, 10 mmol) and Et₃N(10.1 g, 100 mmol) in CH₂Cl₂ (20 mL) was added CH₃COCl (1.73 g, 22 mmol)at 0° C. and stirred for 2 hr at 30° C. The mixture was concentrated andthe residue was dissolved in CH₂Cl₂, washed with water, dried overNa₂SO₄, concentrated to give 0601-199 (1.4 g, 52%) as a yellow solid.LCMS: 271 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.08 (d, J=3.2 Hz, 6H),7.28 (m, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.83 (1H), 9.38 (d, J=3.2 Hz, 2H).

Step 88b:N,N′-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-phenylene)diacetamide(Compound 0602-199)

The title compound 0602-189 was prepared (1.0 g, 63%) as a yellow solidfrom 0601-199 (1.4 g, 5.2 mmol), bis(pinacolato)diboron (2.0 g, 7.8mmol), Pd(dppf)₂Cl₂ (425 mg, 0.52 mmol) and AcOK (1.53 g, 15.6 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 319 [M+1]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 1.28 (s,12H), 2.07 (d, J=6.0 Hz, 6H), 7.41 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.4 Hz,1H), 7.79 (s, 1H), 9.36 (d, J=9.6 Hz, 2H).

Step 88c: Ethyl2-(methyl((2-(2-methyl-3H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-199)

Compound ethyl2-(((2-(3,4-diacetamidophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5-carboxylatewas prepared (260 mg, 75%) as a white solid from 0504-54 (261 mg, 0.58mmol), 0602-199 (240 mg, 0.75 mmol), NaHCO₃ (147 mg, 1.8 mmol) andbis(triphenylphosphine)palladium(II) chloride (41 mg, 0.058 mmol) intoluene (4 mL), ethanol (2 mL) and water (0.5 mL) using a proceduresimilar to that described for compound 0603-107 (Example 34). LCMS: 605[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (m, 3H), 2.11 (s, 6H), 3.27(s, 3H), 3.76 (m, 4H), 3.92 (m, 4H), 4.30 (m, 2H), 5.24 (s, 2H), 7.48(m, 1H), 7.76 (m, 1H), 8.15 (m, 1H), 8.50 (m, 1H), 8.88 (m, 2H), 8.45(m, 2H).

To the solution of above prepared compound (360 mg, 0.6 mmol) in THF (8mL) was added 6M HCl (12 mL) and stirred for 10 hr at 40° C. The mixturewas adjusted to pH8 with saturated aqueous Na₂CO₃ at 0° C., extractedwith ethyl acetate. The organic layer was dried, concentrated andpurified by column chromatography on silica gel (methanol indichloromethane, 2-5 v/v) to give title compound 0603-199 (160 mg, 50%)as a white solid. LC-MS: 545 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.38 (t,J=6.8 Hz, 3H), 2.60 (s, 3H), 3.30 (s, 3H), 3.85 (m, 4H), 4.01 (m, 4H),4.36 (q, J=7.2 Hz, 2H), 5.18 (s, 2H), 7.38 (s, 1H), 7.60 (d, J=8.0 Hz,1H), 8.36 (d, J=8.4 Hz, 1H), 8.67 (s, 1H), 8.92 (s, 2H).

Step 88d:N-hydroxy-2-(methyl((2-(2-methyl-3H-benzo[d]imidazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 199)

The title compound 199 was prepared (38 mg, 24%) as a white solid from0603-199 (160 mg, 0.30 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 230-233° C. LCMS: 532 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 2.51 (s, 3H), 3.24 (s, 3H), 3.78 (m, 4H), 3.93 (m, 4H),5.21 (s, 2H), 7.47 (s, 1H), 7.50 (dd, J=42.8, 8.4 Hz, 1H), 8.25 (t,J=8.8 Hz, 1H), 8.48 (d, J=42.8 Hz, 1H), 8.76 (s, 2H), 9.09 (s, 1H),11.00 (s, 1H), 12.33 (s, 1H).

Example 89 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 186)

Step 89a: 5-Bromo-1H-benzo [d]imidazol-2(3H)-one (Compound 0601-186)

A mixture of 4-bromobenzene-1,2-diamine (3.74 g, 20 mmol), CDI (3.9 g,24 mmol) in 1,4-dioxane (20 mL) was stirred for 1 hr at 40° C. Themixture was filtered and washed with petroleum ether and dichloromethaneto get compound 0601-186 (3.0 g, 70%) as a white solid. LCMS: 213[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 6.86 (d, J=8.0 Hz, 1H), 7.06 (m,1H), 7.08 (m, 1H), 10.77 (s, 2H).

Step 89b:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one(Compound 0602-186)

The title compound 0602-186 was prepared (340 mg, 21%) as a yellow solidfrom 0601-186 (1.3 g, 6 mmol), bis(pinacolato)diboron (2.3 g, 9 mmol),Pd(dppf)₂Cl₂ (490 mg, 0.6 mmol) and AcOK (1.8 g, 18 mmol) using aprocedure similar to that described for compound 0602-107 (Example 34).LCMS: 261 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (s, 12H), 6.91 (d,J=7.6 Hz, 1H), 7.17 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 10.65 (s, 1H),10.77 (s, 1H).

Step 89c: Ethyl2-(methyl((4-morpholino-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-186)

The title compound 0603-186 was prepared (214 mg, 68%) as a white solidfrom 0504-54 (261 mg, 0.58 mmol), 0602-186 (197 mg, 0.75 mmol), NaHCO₃(147 mg, 1.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (41mg, 0.058 mmol) in toluene (4 mL), ethanol (2 mL) and water (0.5 mL)using a procedure similar to that described for compound 0603-107(Example 34). LCMS: 547 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (t,J=6.8 Hz, 3H), 3.27 (s, 3H), 3.77 (m, 4H), 3.91 (m, 4H), 4.28 (q, J=6.8Hz, 2H), 5.23 (s, 2H), 6.99 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.97 (s,1H), 8.08 (d, J=9.2 Hz, 1H), 8.88 (s, 2H), 10.71 (s, 1H), 10.80 (s, 1H).

Step 89d:N-hydroxy-2-(methyl((4-morpholino-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 186)

The title compound 186 was prepared (75 mg, 36%) as a white solid from0603-186 (214 mg, 0.40 mmol) and freshly prepared hydroxylamine methanolsolution (20 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p. 272-275° C. LCMS: 534 [M+1]⁻; ¹H NMR (400MHz, DMSO-d₆) δ 3.23 (s, 3H), 3.77 (m, 4H), 3.91 (m, 4H), 5.20 (s, 2H),7.00 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.98 (s, 1H), 8.09 (d, J=8.4 Hz,1H), 8.75 (s, 2H), 10.71 (s, 1H), 10.82 (s, 1H).

Example 90 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(2-oxoindolin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 194)

Step 90a: 5-Bromoindolin-2-one (Compound 0601-194)

To a mixture of 5-bromoindole-2,3-dione (2.25 g, 10 mmol),ethyleneglycol (45 mL) and hydrazine hydrate (1.06 g, 21.10 mmol) wasadded KOH (1.68 g, 30 mmol). The reaction mixture was stirred at 80° C.for 4 hours. The mixture was cooled to room temperature and poured intoice cold water and the mixture was adjusted to pH 1-2 with 12Nhydrochloric acid and stirred at room temperature for 12 hours. Themixture was filtered and solid was washed with water (5 mL) and dried toget the crude product which was purified by column chromatography onsilica gel (methanol in dichloromethane, 0.5% v/v) to give 0601-194 (785mg, 37%) as a yellow solid. LCMS: 214 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆)δ 3.51 (s, 2H), 6.76 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 2.0 Hz, 1H),7.38 (m, 1H), 10.49 (s, 1H).

Step 90b: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(Compound 0602-194)

The title compound 0602-194 was prepared (323 mg, 83%) as a yellow solidfrom 0601-194 (317 mg, 1.5 mmol), bis(pinacolato)diboron (572 mg, 2.25mmol), Pd(dppf)₂Cl₂ (126 mg, 0.15 mmol) and AcOK (441 mg, 4.5 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 260 [M+1]⁺. ¹H-NMR (400 MHz. DMSO-d₆) δ 1.27 (s,12H), 3.46 (s, 2H), 6.81 (d, J=8.0 Hz, 1H), 7.50 (m, 2H), 10.54 (s, 1H).

Step 90c: Ethyl2-(methyl((4-morpholino-2-(2-oxoindolin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-194)

The title compound 0603-194 was prepared (350 mg, 80%) as a yellow solidfrom 0504-54 (358 mg, 0.80 mmol), 0602-194 (207 mg, 0.80 mmol), Cs₂CO₃(522 mg, 1.60 mmol) and Pd(dppf)₂Cl₂ (65 mg, 0.08 mmol) in 1,4-dioxane(6 mL) and water (0.2 mL) using a procedure similar to that describedfor compound 0603-107 (Example 34). LCMS: 546 [M+1]⁺. ¹H-NMR (400 MHz.DMSO-d₆) δ 1.30 (t, J=7.2 Hz, 3H), 3.27 (s, 3H), 3.57 (m, 2H), 3.76 (m,4H), 3.91 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.23 (s, 2H), 6.90 (d, J=8.4Hz, 1H), 7.44 (s, 1H), 8.28 (m, 2H), 8.88 (s, 2H), 10.59 (s, 1H).

Step 90d:N-hydroxy-2-(methyl((4-morpholino-2-(2-oxoindolin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 194)

The title compound 194 was prepared (85 mg, 25%) as a white solid from0603-194 (350 mg, 0.64 mmol) and freshly prepared hydroxylamine methanolsolution (7.5 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 270° C. (decomposed). LCMS: 533 [M+1]⁺.¹H-NMR (400 MHz, DMSO-d⁶) δ 3.24 (s, 3H), 3.57 (s, 2H), 3.77 (m, 4H),3.91 (m, 4H), 5.20 (s, 2H), 6.90 (m, 1H), 7.42 (m, 1H), 8.26 (m, 2H),8.76 (s, 2H), 10.52 (s, 1H).

Example 91 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 196)

Step 91a: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Compound 0602-196)

The title compound 0602-196 was prepared (400 mg, 30%) as a yellow solidfrom 4-bromopyrazole (1 g, 6.8 mmol), bis(pinacolato)diboron (2.6 g,10.2 mmol), Pd(dppf)₂Cl₂ (166 mg, 0.2 mmol) and AcOK (g, 20.4 mmol)using a procedure similar to that described for compound 0602-107(Example 34). LCMS: 195 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.25 (s,12H), 7.93 (s, 2H), 13.09 (s, 1H).

Step 91b: Ethyl2-(methyl((4-morpholino-2-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-196)

The title compound 0603-196 was prepared (150 mg, 47%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 0602-196 (259 mg, 1.33 mmol), NaHCO₃(168 mg, 2.0 mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.03 mmol) in toluene (5 mL),ethanol (3 mL) and water (1.3 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 481 [M+1]¹. ¹H NMR(400 MHz, DMSO-d₆) δ 1.30 (t, J=6.8 Hz, 3H), 3.26 (s, 3H), 3.73 (m, 4H),3.88 (m, 4H), 4.28 (q, J=7.6 Hz, 2H), 5.21 (s, 2H), 7.38 (s, 1H), 8.04(s, 1H), 8.30 (s, 1H), 8.88 (s, 2H), 13.07 (s,1H).

Step 91c:N-hydroxy-2-(methyl((4-morpholino-2-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 196)

The title compound 196 was prepared (59 mg, 41%) as a yellow solid from0603-196 (150 mg, 0.31 mmol) and freshly prepared hydroxylamine methanolsolution (8 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 214-217° C. LCMS: 468 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 3.23 (s, 3H), 3.73 (m, 4H), 3.87 (m, 4H), 5.18 (s, 2H), 7.35(s, 1H), 8.05 (s, 1H), 8.30 (s, 1H), 8.74 (s, 2H), 9.07 (s, 1H), 11.11(s, 1H), 13.07 (s,1H).

Example 92 Preparation ofN-hydroxy-2-(methyl((4-morpholino-2-(1H-pyrrol-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 197)

Step 92a: 3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (Compound 0601-197)

A solution n-BuLi in THF (2.5 M, 19.6 mL, 49 mmol) was added to astirred solution of pyrrole (3 g, 44.7 mmol) in anhydrous THF (20 mL) at−78° C. in an N₂ atmosphere. Then the mixture was warmed to roomtemperature and stirred at this temperature for 10 min. The mixture wascooled again to −78° C., and chlorotriisopropylsilane (10.5 g, 44.7mmol)was added dropwisely with stirring. Then the mixture was warmed to roomtemperature and stirred for additional 30 min., diluted with water (200mL), extracted with ether (200 mL). The organic layer was washed withwater (2×100 mL) and brine (100 mL), dried over Na₂SO₄, concentrated togive crude 1-(triisopropylsilyl)-1H-pyrrole (11 g, 100%) as a oil. LCMS:224 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 0.98 (m, 18H), 1.40 (m 3H), 6.20(m, 2H), 6.80 (m, 2H).

To a solution of the above prepared 1-(triisopropylsilyl)-1H-pyrrole(5.85 g, 26.2 mmol) in THF (50 mL) was added NBS (4.66 g, 26.2 mmol) at−78° C. and the resulting mixture was stirred at −78° C. for 2 h. Themixture was warmed to room temperature and stirred for additional 1 h.The mixture was concentrated and purified by column chromatography onsilica gel (petroleum) to give compound 0601-197 (6.8 g, 63%) as acolorless oil. LCMS: 302 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 0.98 (m,18H), 1.47 (m 3H), 6.26 (d, J=6.0 Hz, 1H), 6.82 (m, 1H), 6.89 (m, 1H).

Step 92b: 1-(Triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (Compound0602-197)

A solution n-BuLi in THF (2.5 M, 1.58 mL, 3.96 mmol) was added to astirred solution of 0601-197 (1 g, 3.31 mmol) in anhydrous THF (20 mL)at −78° C. in an N₂ atmosphere. The resulting mixture was stirred atthis temperature for 30 min. To the mixture was added trimethyl borate(687 mg, 6.6mmol) dropwise. Then the mixture was warmed to roomtemperature and stirred for additional 1 h. The mixture was diluted withwater (200 mL), extracted with ethyl acetate (200 mL). The organic layerwas washed with water (2×100 mL) and brine (100 mL), dried over Na₂SO₄,concentrated to give crude compound 0602-197 (280 mg, 32%) as a oilwhich was used in next step directly without further purification. LCMS:268 [M+1]⁺.

Step 92c: Ethyl2-(methyl((4-morpholino-2-(1H-pyrrol-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxylate(Compound 0603-197)

The title compound 0603-197 was prepared (260 mg, 81%) as a yellow solidfrom 0504-54 (300 mg, 0.67 mmol), 0602-197 (0.8 g), NaHCO₃ (168 mg, 2.0mmol), (Ph₃P)₂PdCl₂ (23 mg, 0.03 mmol) in toluene (5 mL), ethanol (3 mL)and water (1 mL) using a procedure similar to that described forcompound 0603-107 (Example 34). LCMS: 480 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.28 (t, J=7.2 Hz, 3H), 3.24 (s, 3H), 3.71 (m, 4H), 3.84 (m,4H), 4.27 (q, J=7.2 Hz, 2H), 5.18 (s, 2H), 6.65 (s, 1H), 6.77 (s, 1H),7.33 (s, 1H), 7.47 (s, 1H), 8.86 (s, 2H), 11.07 (s, 1H).

Step 92d:N-Hydroxy-2-(methyl((4-morpholino-2-(1H-pyrrol-3-yl)thieno[3,2-d]pyrimidin-6-yl)methyl)amino)pyrimidine-5-carboxamide(Compound 197)

The title compound 197 was prepared (63 mg, 25%) as a yellow solid from0603-197 (260 mg, 0.54 mmol) and freshly prepared hydroxylamine methanolsolution (10 mL) using a procedure similar to that described forcompound 3 (Example 1). m.p.: 175-189° C. LCMS: 467 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 3.21 (s, 3H), 3.72 (m, 4H), 3.83 (m, 4H), 5.15 (s, 2H),6.65 (s, 1H), 6.75 (s, 1H), 7.30 (s,1H), 7.46 (s, 1H), 8.73 (m, 2H),9.05 (s, 1H), 11.05 (s, 1H), 11.11 (s, 1H).

Example 93 Preparation of2-((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide(Compound 211)

Step 93a: Ethyl2-((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)pyrimidine-5-carboxylate(Compound 0603-211)

The title compound 0603-211 was prepared (65 mg, 22%) as a yellow solidfrom 0504-53 (256 mg, 0.59 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenylamine (155 mg, 0.71mmol), Cs₂CO₃ (577 mg, 1.77 mmol) and Pd(dppf)₂Cl₂ (48 mg, 0.06 mmol) in1,4-dioxane (6 mL) and water (0.2 mL) using a procedure similar to thatdescribed for compound 0603-107 (Example 34). LCMS: 492 [M+1]⁺. ¹H-NMR(400 MHz. DMSO-d₆) δ 1.29 (t, J=7.2 Hz, 3H), 3.75 (m, 4H), 3.89 (m, 4H),4.27 (q, J=7.2 Hz, 2H), 4.87 (d, J=6.0 Hz, 2H), 5.53 (s, 2H), 6.60 (m,2H), 7.28 (s, 1H), 8.09 (m, 2H), 8.83 (m, 3H).

Step 93b:2-((2-(4-aminophenyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-hydroxypyrimidine-5-carboxamide(Compound 211)

The title compound 211 was prepared (28 mg, 45%) as a yellow solid from0603-211 (65 mg, 0.13 mmol) and freshly prepared hydroxylamine methanolsolution (6 mL) using a procedure similar to that described for compound3 (Example 1). m.p.: 217-223° C. LCMS: 479 [M+]⁺. ¹H-NMR (400 MHz.DMSO-d₆) δ 3.76 (m, 4H), 3.89 (m, 4H), 4.84 (d, J=5.6 Hz, 2H), 5.53 (s,2H), 6.60 (m, 2H), 7.27 (s, 1H), 8.90 (m, 2H), 8.51 (t, J=5.6 Hz, 1H),8.66 (s, 2H), 9.05 (s, 1H), 11.09 (s, 1H).

Biological Assays:

The following assays are used to determine the IC₅₀ of compounds of thepresent invention as it identifies inhibitors of PI3 kinases:

(a) An In Vitro assay which Determines the Ability of a Test Compound toInhibit PI3Kα.

Activity of PI3Kα was measured using fluorescence polarization assay.P13Kα, a complex of N-terminal histidine-tagged recombinant full-lengthhuman p110α and untagged recombinant full length human p85α werecoexpressed in a Baculovirus infected Sf9 cell expression system.(GenBank Accession No. for p110α, U79143; for p85α, XM_(—)043865). Theproteins are purified by one-step affinity chromatography usingglutathione-agarose. A competition assay was performed to measure theamount of PIP3 generated from PIP2 in the presence of purifiedrecombinant PI3Kα (p110α/p85α). PI3Kα was incubated with 10 μM PIP2substrate in the reaction buffer (20 mM HEPES, pH 7.5, 10 mM NaCl, 4 mMMgCl2, 2 mM DTT, 10 μM ATP and 1% DMSO) for 1 hour at 30° C. Thereaction product was then mixed with a PIP3 detector protein and thefluorescent PIP3 probe. Polarization (mP) values decrease as fluorescentprobe binding to the PIP3 detector is displaced by PIP3 produced byenzymatic activity and the amount of unbound fluorescent probe in themixture increases. Polarization degrees (mP) value was determined usingmicroplate reader with background subtraction.

(b) An In Vitro Assay which Determines the Ability of a Test Compound toInhibit PI3Kβ.

Activity of PI3Kβ was measured using time-resolved fluorescenceresonance energy transfer (TR-FRET) assay utilizing homogenous timeresolved fluorescence (HTRF) technology. P13Kβ, a complex of N-terminalhistidine-tagged recombinant full-length human p110β and untaggedrecombinant full length human p85α were coexpressed in a Baculovirusinfected Sf21 cell expression system. (GenBank Accession No. for p110β,NM_(—)006219; for p85α, XM_(—)043865) The proteins are purified byone-step affinity chromatography using glutathione-agarose. Acompetition assay was performed to measure the amount of PIP3 generatedfrom PIP2 in the presence of purified recombinant PI3Kbeta (p110β/p85α).PI3Kβ was incubated with 10 μM PIP2 substrate in the reaction buffer (20mM HEPES, pH 7.5, 10 mM NaCl, 4 mM MgCl₂, 2 mM DTT, 10 μM ATP and 1%DMSO) for 30 minutes at 30° C. The reaction product was then mixed witha PIP3 detector protein, europium-labeled antibody, biotin-labeled PIP3probe and allophycocyanin-labeled Streptavidin. A sensor complex isformed to generate a stable TR-FRET signal in the reaction mixture. Thissignal intensity decrease as biotin-labeled probe binding to the PIP3detector is displaced by PIP3 produced by enzymatic activity and theamount of unbound biotin-labeled PIP3 probe in the mixture increases.TR-FRET signal was determined using microplate reader with backgroundsubtraction.

(c) An In Vitro Assay which Determines the Ability of a Test Compound toInhibit PI3Kδ.

Activity of PI3Kδ was measured using fluorescence polarization assay.P13Kδ, a complex of N-terminal histidine-tagged recombinant full-lengthhuman p110δ and untagged recombinant full length human p85α werecoexpressed in a Baculovirus infected Sf9 cell expression system.(GenBank Accession No. for p110δ, NM_(—)005026). The proteins arepurified by one-step affinity chromatography using glutathione-agarose.A competition assay was performed to measure the amount of PIP3generated from PIP2 in the presence of purified recombinant PI3Kδ(p110δ/p85α). PI3Kδ was incubated with 10 μM PIP2 substrate in thereaction buffer (20 mM HEPES (pH 7.5), 10 mM NaCl, 4 mM MgCl₂, 2 mM DTT,10 μM ATP and 1% DMSO) for 1 hour at 30° C. The reaction product wasthen mixed with a PIP3 detector protein and the fluorescent PIP3 probe.Polarization (mP) values decrease as fluorescent probe binding to thePIP3 detector is displaced by PIP3 produced by enzymatic activity andthe amount of unbound fluorescent probe in the mixture increases.Polarization degrees (mP) value was determined using microplate readerwith background subtraction.

(d) An In Vitro Assay which Determines the Ability of a Test Compound toInhibit PI3Kγ.

Activity of PI3Kγ was measured using time-resolved fluorescenceresonance energy transfer (TR-FRET) assay utilizing homogenous timeresolved fluorescence (HTRF) technology. N-terminal histidine taggedhuman P13Kδ was expressed in a Baculovirus infected Sf9 cell expressionsystem. (GenBank Accession AF327656). The proteins are purified byone-step affinity chromatography using glutathione-agarose. Acompetition assay was performed to measure the amount of PIP3 generatedfrom PIP2 in the presence of purified recombinant PI3Kγ (p120γ). PI3Kγ(2 nM) was incubated with 10 μM PIP2 substrate in the reaction buffer(20 mM HEPES, pH 7.5, 10 mM NaCl, 4 mM MgCl₂, 2 mM DTT, 10 μM ATP and 1%DMSO) for 30 minutes at 30° C. The reaction product was then mixed witha PIP3 detector protein, europium-labeled antibody, biotin-labeled PIP3probe and allophycocyanin-labeled Streptavidin. A sensor complex isformed to generate a stable TR-FRET signal in the reaction mixture. Thissignal intensity decrease as biotin-labeled probe binding to the PIP3detector is displaced by PIP3 produced by enzymatic activity and theamount of unbound biotin-labeled PIP3 probe in the mixture increases.TR-FRET signal was determined using microplate reader with backgroundsubtraction.

(e) An In Vitro Assay which Determines the Ability of a Test Compound toInhibit HDAC Enzymatic Activity.

HDAC inhibitory activity was assessed using the Biomol Color de Lyssystem (AK-500, Biomol, Plymouth Meeting, Pa.). Briefly, HeLa cellnuclear extracts were used as a source of HDACs. Differentconcentrations of test compounds were serially diluted indimethylsulphoxide (DMSO) and added to HeLa cell nuclear extracts in thepresence of a colorimetric artificial substrate. Final assay conditioncontained 50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl₂.Reactions were carried in room temperature (25° C.) for 1 hour beforeaddition of developer for termination. Relative enzyme activity wasmeasured in the WALLAC Victor II 1420 microplate reader as floorescenceintensity (excitation: 350-380 nm; emission: 440-460 nm). Data wereanalyzed using GraphPad Prism (v4.0a) with a sigmoidal dose responsecurve fitting for IC50 calculation.

(f) An In Vitro Assay which-Determines the Ability of a Test Compound toInhibit mTor Serine/Threonine Protein Kinase.

The ability of compounds to inhibit mTor activity was assayed usingstandard radioisotope assay for kinase. Briefly, FLAG-tagged,recombinant full-length human mTor (GenBank accession No. NM_(—)004958)was expressed using baculovirus expression system in Sf21 cells andpurified using antibody affinity column. Purified enzyme was incubatedwith c-terminal fragment of p70S6K as it's substrate in the presence ofATP. p33 ATP tracers were included in the assay to monitor the enzymeactivity. Final assay condition was with 50 mM HEPES pH 7.5, 1 mM EGTA,0.01% Tween 20, 2 mg/ml substrate, 3 mM Manganese Chloride and 70 uM ofATP and was carried out at room temperature for 40 minutes. The reactionwas then stopped by the addition of 3% phosphoric acid solution. 10 ulof the reaction was spotted onto a P30 filtermat and washed three timesfor 5 minutes in 75 mM phosphoric acid and once in methanol prior todrying and scintillation counting. Different concentrations of compoundswere added to reaction to assess the activity of compounds to inhibitmTor kinase. IC50 was calculated using Prism software with sigmoidaldose-response curve fitting.

The following TABLE B lists compounds representative of the inventionand their activity in HDAC, PI3K and m-TOR assays. In these assays, thefollowing grading was used: I>10 μM, 10 μM≧II≧1 μM, 1 μM≧III≧0.1 μM, andIV<0.1 μM for IC₅₀.

TABLE B Compound No. HDAC PI3Kα PI3Kβ PI3Kγ PI3Kδ m-TOR 3 IV I 4 IV I 5IV I 7 III III 8 IV I 9 IV I 11 II 12 III IV 13 III III 14 IV IV IV IVIII II 15 IV III I 16 III IV II 18 IV III 19 IV III 20 IV III 30 III I31 III I 32 III I 34 III I 35 IV I 36 IV I 41 IV III 42 IV II 43 IV IIII 44 III IV 45 I IV 46 II III 48 IV IV 49 III IV 50 IV IV 51 III IV 53IV IV IV IV IV 54 IV IV IV IV IV 60 IV I 61 IV I 62 IV I 63 IV I 65 IVIII 66 IV III 67 IV III 68 IV III 69 IV IV II 70 IV IV III 71 IV III 73IV III 74 IV III 75 III IV 76 IV IV 78 IV III 79 IV IV 80 III IV 81 IIIV 83 II III 84 IV IV 85 IV III 86 IV IV IV 87 IV IV II 88 III IV 89 IVIV II 90 IV IV 91 IV IV 92 IV IV 93 III III 94 IV IV 95 III IV 96 IV IV97 IV IV 98 IV IV 99 IV IV III 101 I III III 102 III III III 103 IV III104 III IV 105 III I 106 II IV 107 IV II 108 IV II 109 IV IV III 110 IVIV IV 112 IV IV 114 IV III 115 IV IV IV 116 IV IV IV 117 IV IV II 119 IVIV 120 IV IV III 121 IV IV II 122 IV IV 124 IV IV 125 IV IV 129 IV I 130IV III 131 IV I 132 IV IV IV 133 IV III 134 IV III 135 IV III 136 I I137 IV II 138 IV IV IV 139 IV III 140 IV III 141 IV III 142 IV III III143 IV III 144 IV II 146 IV I 147 IV I 148 IV I 149 IV I 150 IV IV IV151 IV I 152 IV I 153 IV I 154 IV I 155 IV I 156 IV III 157 IV IV IV 158IV I 159 IV II 160 IV I 161 IV III 162 IV II 163 IV III 164 IV IV 165 IVI 166 IV I 167 IV III 168 IV II 176 IV III 177 IV I 178 IV I I 181 IV III 182 IV II 183 IV I I 184 IV II III 186 IV I 187 IV IV 191 IV 192 IVIII 193 IV I 194 IV I 196 IV III 197 IV IV 199 IV IV 200 IV I 201 IV III202 IV III 203 III III 204 III III 206 IV III 207 IV III 209 IV I 210III III 211 IV III 214 IV 215 IV IIICell Proliferation Assay:

Cancer cell lines were plated at 5,000 to 10,000 per well in 96-wellflat bottomed plates with various concentration of compounds. The cellswere incubated with compounds for 72 hours in the presence of 0.5% offetal bovine serum. Growth inhibition was accessed by adenosinetriphosphate (ATP) content assay using Perkin Elmer ATPlite kit. ATPliteis an ATP monitoring system based on firefly luciferase. Briefly, 25 μlof mammalian cell lysis solution was added to 50 μl of phenol red-freeculture medium per well to lyse the cells and stabilize the ATP. 25 μlof substrate solution was then added to the well and subsequently theluminescence was measured.

The following TABLE C lists compounds representative of the inventionand their antiproliferative activity in cell-based assays. In theseassays, the following grading was used: I>10 μM, 10 μM≧II≧1 μM, 1μM≧III≧0.1 μM, and IV<0.1 μM for IC₅₀.

TABLE C Compound No. HCT-118 BT-474 Sk-Mel-28 H1993 53 III IV III III 54IV IV IV IV 69 IV IV IV IV 70 IV IV IV IV 75 III III III III 76 III IIIIII III 86 III III II 87 III II III II 90 IV III II 91 II II I 92 IV IVIII 99 I III III I 109 IV IV IV 110 IV IV IV IV 115 IV IV IV IV 116 IVIV IV IV 117 IV IV IV IV 125 IV IV III III 132 IV IV IV IV 138 IV IV IVIV 150 IV IV IV IV

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by formula (I);

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt, or prodrug thereof, wherein

represents a single or double bond; q, r and s are independently 0 or 1,wherein at least one of q, r and s is 1; t is 0 or 1; n is 0, 1, 2, 3 or4; p is 0, 1 or 2; X is CR₁, N(R₈), S or O; Y is CR₁, S or O; providedthat X and Y are not both CR₁; G₁ is CR₁, S, O, NR₁₀ or NS(O)₂R₁₀; G₂ issubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or, substituted or unsubstituted heterocyclic; G₃ issubstituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, or, substituted or unsubstituted C₂-C₈ alkynyl; each R₈is independently hydrogen, acyl, aliphatic or substituted aliphatic;each R₁ and R₂ is independently selected from absent, hydrogen, hydroxy,amino, halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic; R_(a) is optionally substituted alkyl, optionallysubstituted aryl or optionally substituted heteroaryl; R_(b) ishydrogen, optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; or R_(a) and R_(b), together with thenitrogen atom to which they are attached, form an optionally substitutedheterocyclic group; R₁₀ is selected from hydrogen, hydroxy, amino,alkoxy, alkylamino, dialkylamino, sulfonyl, acyl, aliphatic, substitutedaliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic; B is a linker; and C is

 where W is O or S; J is O, NH or NCH₃; and R₃₁ is hydrogen or loweralkyl.
 2. A compound of claim 1 wherein B is selected from the groupconsisting of alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl,alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl,alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl,alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl,alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl,alkenylheteroarylalkenyl, alkenylheteroarylalkynyl,alkynylheteroarylalkyl, alkynylheteroarylalkenyl,alkynylheteroarylalkynyl, alkylheterocyclylalkyl,alkylheterocyclylalkenyl, alkylhererocyclylalkynyl,alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl,alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl,alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl,alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, oralkynylhereroaryl, in each of which one or more methylenes can beinterrupted or terminated by O, S, S(O), SO₂, N(R₈), C(O), substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocyclic, wherein R₈ is as defined inclaim
 1. 3. A compound of claim 1, represented by formula (II):

wherein X, Y, G₁, G₂, R₁, R₂, R₈, n, p, q, r, s, B and C are as definedas in claim
 1. 4. A compound of claim 3, wherein G₂ is optionallysubstituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl orbenzimidazolyl.
 5. A compound of claim 4, wherein G₂ is a phenyl,pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl group, whereinsaid group is substituted by a hydroxyl, hydroxymethyl, amino,acylamino, acetylamino or methylamino group.
 6. A compound of claim 1,represented by formula (IV), (V), (VI) or (VII);

or the geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, or prodrugs thereof, wherein

represents a single or double bond; G₁, G₂, R₁, R₂, R₈, n, p, q, r, s, Band C are as defined as in claim 1; m is 0, 1, 2 or 3; G₄ is NR₈, S orO; R₃ is selected from absent, hydrogen, hydroxy, amino, halogen,alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl,aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic.
 7. Acompound of claim 6, wherein G₂ is selected from the group below:

wherein R₃, R₈ and m have the meanings set forth in claim
 6. 8. Acompound of claim 7, wherein m is 1 and R₃ is selected from the groupconsisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino andmethylamino.
 9. A compound of claim 1, represented by formula (X), (XI),(XII) or (XIII);

or a geometric isomer, enantiomer, diastereomer, racemate,pharmaceutically acceptable salt, or prodrug thereof, wherein

represents a single or double bond; G₁, G₂, R₁, R₂, R₈, R_(a), R_(b), n,p, q, r, s, B and C are as defined in claim 1; m is 0, 1, 2 or 3; R₃ isselected from absent, hydrogen, hydroxy, amino, halogen, alkoxy,alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl, aliphatic,substituted aliphatic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic; G₄ is NR₈, S orO; and o is 1,2,3,4,5, 6, 7 or
 8. 10. A compound of claim 9, wherein G₂is selected from the group below:

wherein R₃, R₈ and m have the meanings set forth in claim
 9. 11. Acompound of claim 10, wherein m is 1 and R₃ is selected from the groupconsisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino andmethylamino.
 12. A compound of claim 1, represented by formula (XIV),(XV), (XVI) or (XVII);

wherein G₁, G₂, n, p, B, C, R₁, R₂, and R₈ are as defined in claim 1; mis 0, 1, 2 or 3; and R₃ is selected from absent, hydrogen, hydroxy,amino, halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂,sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic.
 13. A compound of claim 12, wherein G₂ is selected fromthe group below:

wherein R₃, R₈ and m have the meanings set forth in claim
 12. 14. Acompound of claim 13, wherein m is 1 and R₃ is selected from the groupconsisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino andmethylamino.
 15. A compound of claim 1, represented by formula XVIII orXIX;

wherein G₂, n, p, B, C, R₁, R₂, and R₈ are as defined in claim 1; m is0, 1, 2 or 3; and R₃ is selected from absent, hydrogen, hydroxy, amino,halogen, alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl,aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic. 16.A compound of claim 15, wherein G₂ is selected from the group below:

wherein R₃, R₈ and m have the meanings set forth in claim
 15. 17. Acompound of claim 16, wherein m is 1 and R₃ is selected from the groupconsisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino andmethylamino.
 18. A compound of claim 1, wherein B is selected from:

wherein d and e are independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and R₁₀₀is selected from hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl andC₃-C₈ cycloalkyl.
 19. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein G₂ is optionallysubstituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl orbenzimidazolyl; and R₈ is hydrogen or methyl.
 20. A compound of claim19, wherein G₂ is selected from the group below:

wherein R₃ is selected from absent, hydrogen, hydroxy, amino, halogen,alkoxy, alkylamino, dialkylamino, CF₃, CN, NO₂, sulfonyl, acyl,aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; m is0, 1, 2 or 3; and R₈ has the meaning set forth in claim
 19. 21. Acompound of claim 20, wherein m is 1 and R₃ is selected from the groupconsisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino andmethylamino.
 22. A compound selected from the compounds delineated inTable A or a pharmaceutically acceptable salt or prodrug thereof: TABLEA Compound No. Structure 53

54

69

73

74

75

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

211

215


23. A pharmaceutical composition comprising as an active ingredient acompound of claim 1 and a pharmaceutically acceptable carrier.
 24. Acompound having the structure:

or a pharmaceutically acceptable salt or prodrug thereof.
 25. Apharmaceutical composition comprising as an active ingredient a compoundof claim 19 and a pharmaceutically acceptable carrier.